This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cabrera-Vera, T. M. Articles by Hamm, H. E. Search for Related Content PubMed PubMed Citation Articles by Cabrera-Vera, T. M. Articles by Hamm, H. E. Pubmed/NCBI databases Substance via MeSH

Insights into G Protein Structure, Function, and Regulation

Department of Molecular Pharmacology and Biological Chemistry (T.M.C.-V., J.V., T.O.T., M.M., A.P., H.E.M.), Institute for Neuroscience, Northwestern University, Chicago, Illinois 60611; Department of Molecular Pharmacology (M.R.M., H.E.M.), Vanderbilt University Medical Center, Nashville, Tennessee 37232; and Department of Psychiatry, Neurobiology, Pharmacology, and Biotechnology (M.R.M.), University of Pisa, Pisa, 56057, Italy

Correspondence: Address all correspondence and requests for reprints to: Heidi E. Hamm, Ph.D., Department of Pharmacology, Vanderbilt University Medical Center, 442 Robinson Research Building, 23rd and Pierce Drive, Nashville, Tennessee 37232. E-mail: heidi.hamm{at}mcmail.vanderbilt.edu

	Abstract

Top Abstract I. Introduction II. G Protein Structure III. Molecular Basis for... IV. Structural Determinants of... V. Receptor-Independent... VI. The Receptor-G{alpha}... VII. G{alpha} Interaction with... VIII. Gß{gamma}... IX. Molecular Basis for... X. Regulation of G... XI. Advances for the... References

 
In multicellular organisms from Caenorhabditis elegans to Homo sapiens, the maintenance of homeostasis is dependent on the continual flow and processing of information through a complex network of cells. Moreover, in order for the organism to respond to an ever-changing environment, intercellular signals must be transduced, amplified, and ultimately converted to the appropriate physiological response. The resolution of the molecular events underlying signal response and integration forms the basis of the signal transduction field of research. An evolutionarily highly conserved group of molecules known as heterotrimeric guanine nucleotide-binding proteins (G proteins) are key determinants of the specificity and temporal characteristics of many signaling processes and are the topic of this review. Numerous hormones, neurotransmitters, chemokines, local mediators, and sensory stimuli exert their effects on cells by binding to heptahelical membrane receptors coupled to heterotrimeric G proteins. These highly specialized transducers can modulate the activity of multiple signaling pathways leading to diverse biological responses. In vivo, specific combinations of G- and Gß-subunits are likely required for connecting individual receptors to signaling pathways. The structural determinants of receptor-G protein-effector specificity are not completely understood and, in addition to involving interaction domains of these primary acting proteins, also require the participation of scaffolding and regulatory proteins.

I. Introduction

II. G Protein Structure

III. Molecular Basis for G Protein Activation

IV. Structural Determinants of Receptor-G Protein Specificity

V. Receptor-Independent Activators of G Protein Signaling (AGS Proteins)

VI. The Receptor-G Protein Interface as a Therapeutic Target

VII. G Interaction with Effectors

VIII. Gß Interaction with Effectors

A. Gß-Dimer composition directs effector and receptor coupling

B. Structural determinants of effector specificity

C. Novel Gß-effectors

D. Additional role for Gß₅

IX. Molecular Basis for G Protein Inactivation

A. Intrinsic GTPase activity

B. G Interaction with GTPase-activating proteins (GAPs)

X. Regulation of G Protein Function by Covalent Modification

A. G protein lipidation

B. The role of lipid modifications in G protein membrane association and consequent signaling functions

XI. Advances for the Future: Investigating the Dynamic Nature of G Protein Signaling

	I. Introduction

Top Abstract I. Introduction II. G Protein Structure III. Molecular Basis for... IV. Structural Determinants of... V. Receptor-Independent... VI. The Receptor-G{alpha}... VII. G{alpha} Interaction with... VIII. Gß{gamma}... IX. Molecular Basis for... X. Regulation of G... XI. Advances for the... References

 
WHEN A LIGAND such as a hormone, neurotransmitter, or glycoprotein interacts with a heptahelical receptor on the surface of the cell, the ligand either stabilizes or induces a conformation in the receptor that activates a heterotrimeric G protein (composed of -, ß-, and -subunits) on the inner membrane surface of the cell (1). In the inactive heterotrimeric state, GDP is bound to the G-subunit. Upon activation, GDP is released, GTP binds to G, and subsequently G-GTP dissociates from Gß and from the receptor (Fig. 1). Both G-GTP and Gß are then free to activate downstream effectors. The duration of the signal is determined by the intrinsic GTP hydrolysis rate of the G-subunit and the subsequent reassociation of G-GDP with Gß (1, 2). This article will review current knowledge and recent progress in defining the molecular mechanisms that regulate the activity and specificity of G protein signaling cascades. In addition, we will briefly discuss the use of dynamic experimental approaches that are likely to provide new insights into G protein regulation in the future.

View larger version (36K): [in this window] [in a new window]   FIG. 1. Receptor-mediated G protein activation. The interaction of an endogenous ligand with its cell surface receptor (R) facilitates the coupling of the activate receptor (R*) with intracellular heterotrimeric G proteins. The R*-G protein coupling promotes the exchange of GDP for GTP on the G-subunit. G-GTP then dissociates from Gß and R*. Both subunits are free to modulate the activity of a wide variety of intracellular effectors. Termination of the signal occurs when the -phosphate of GTP is removed by the intrinsic GTPase activity of the G-subunit, leaving GDP in the nucleotide binding pocket on G. G-GDP then reassociates with Gß and the cycle is complete. RGS proteins accelerate the intrinsic GTPase activity of G-subunits, thereby reducing the duration of signaling events.

	II. G Protein Structure

Top Abstract I. Introduction II. G Protein Structure III. Molecular Basis for... IV. Structural Determinants of... V. Receptor-Independent... VI. The Receptor-G{alpha}... VII. G{alpha} Interaction with... VIII. Gß{gamma}... IX. Molecular Basis for... X. Regulation of G... XI. Advances for the... References

According to current knowledge, 16 genes encode for G-subunits, five genes encode for Gß-, and 12 genes encode for G-subunits (10). Classically, G proteins are divided into four families based on similarity of their -subunits: G_i/o, G_s, G_q/11, and G_12/13 (Table 1). G-subunits contain two domains: a GTPase domain that is involved in the binding and hydrolysis of GTP and a helical domain that buries the GTP within the core of the protein (Fig. 2A). The helical domain is the most divergent domain among G families and may play a role in directing specificity of receptor- and effector-G protein coupling. Comparison of G_t-GDP and G_t-GTPS crystal structures has revealed the presence of three flexible regions, designated switches I, II, and III, which become more rigid and well ordered in the GTP-bound active conformation (3, 4). Little is known about the structure of the extreme amino (N-) and carboxy (C-) terminal domains of G-subunits because in the isolated G protein crystal structures solved thus far, the N and C termini of G were either removed from the protein or disordered (3, 4, 5, 6). However, in two separate crystal structures of heterotrimeric complex, the N-terminal helix is ordered by its interaction with the ß-propeller domain of Gß (Refs. 7 and 8 and Fig. 2A). Biochemical studies suggest that these terminal regions play a key role in the activation process and in directing specific protein-protein interactions, as is discussed in the following section.

View this table: [in this window] [in a new window]   TABLE 1. Classification of G-subtypes and their effectors

View larger version (52K): [in this window] [in a new window]   FIG. 2. Schematic diagrams of Gt, the RGS4-Gi1 complex, and effector contact sites on Gß. A, Ribbon diagrams depicting the probable membrane orientation of heterotrimeric Gt. The refined rhodopsin structure is from Ref. 240 [Protein databank (PDB) file 1F88]. Gt (purple); GDP molecule (red); Gß (green); G (yellow); rhodopsin helices [color gradient from red (N terminus) to navy blue (C terminus]; the retinal molecule within rhodopsin (magenta). Diagrams were generated using coordinates from PDB files (1GOT and 1BOK) and visualized with WebLab ViewerPro. B, Ribbon diagram depicting the RGS4/Gi1 complex. RGS 4 (green); Gi1. (red); Gi1 ß-sheets (cyan); GTP molecule (magenta). Diagrams were generated using coordinates from PDB file 1AGR and visualized with WebLab ViewerPro. C, Solvent-accessible surface model of Gß11 highlighting residues identified as important mediators of effector interaction (26 ). The crystal coordinates of Gß11 [PDB entry 1TBG] were used to generate a surface model of the dimer in Graphical Representation and Analysis of Structural Properties. Gß (gray); G (pink). The area on Gß that is covered by G in the G protein heterotrimer crystal structure is highlighted in light green. The effector-interacting residues on Gß are circled with colored dashed lines as follows: ß-adrenergic receptor kinase (orange); PLCß2 (red); AC II (green); K+ channel (blue); Ca2+ channel (yellow). G-GDP, when bound to Gß, covers all these distinct yet partially overlapping effector interaction regions on Gß and, thus, blocks Gß regulation of all the effectors. [Figure 2C reprinted with permission from Ford et al.: Science 280:1271–1274, 1998 (26 ). © 1988 American Association for the Advancement of Science.]

	III. Molecular Basis for G Protein Activation

Top Abstract I. Introduction II. G Protein Structure III. Molecular Basis for... IV. Structural Determinants of... V. Receptor-Independent... VI. The Receptor-G{alpha}... VII. G{alpha} Interaction with... VIII. Gß{gamma}... IX. Molecular Basis for... X. Regulation of G... XI. Advances for the... References

 
The rate-limiting step in G protein activation is the release of GDP from the nucleotide-binding pocket. GDP is spontaneously released from the heterotrimeric G protein at a rate that varies depending on the G-subunit. For example, the G_o GDP release rate (k_off) is 0.19 min^-1 whereas the G_i2 release rate is 0.072 min^-1 (11). However, the inactive state of the G-subunits is controlled by Gß binding. Higashijima et al. (12) showed that in the absence of Mg²⁺, Gß increases the affinity of G_o for GDP about 300-fold. GDP release is greatly facilitated by receptor activation of the G protein (13). Mutations (14, 15, 16) of residues in the critical TCAT guanine nucleotide-binding motif present in the ß6-5 loop of the GTPase domain (4) enhance receptor-independent spontaneous GDP release. Iiri et al. (14) identified such an activating mutation in G_s (A³⁶⁶S) in male patients with pseudohypoparathyroidism and gonadotropin-independent precocious puberty. Enhanced GDP release was also observed when similar mutations were generated in G_i [A³²⁶S; (15)] and G_o [C³²⁵S; (16)] suggesting that this region serves as a common mediator of GDP release. Posner et al. (15) also demonstrated that GDP release can occur without inducing a large conformational change in G.

In addition to the TCAT motif, most recent work has identified residues within the helical domain as well as within the N- and C-terminal domains of G-subunits that are also integral mediators of spontaneous GDP release. For example, in G_t mutation of three residues located in the inward-facing surface of the 5-helix causes a dramatic increase of basal nucleotide exchange rate in addition to enhanced receptor-catalyzed nucleotide exhange rate (17). Mutation of five residues within the switch IV helical domain in G_s decreases the rate of GDP release, GTPS binding, and GTP hydrolysis (18) and disruption of contacts between the helical and GTPase domains also influences basal GDP dissociation rates (19, 20). By fluorescently labeling the C-terminal residue Cys³⁴⁷ of a G_t/G_i chimera, Yang et al. (21) determined that the C terminus moves into a more hydrophobic environment upon AlF₄^- activation. The authors suggest that this movement may reflect an interaction between the C terminus and the 2-ß4 loop of G_t/G_i. In addition, these divergent terminal domains have been implicated as the source of variation in the intrinsic GDP release rates among G-subunits. Substitution of 31 N-terminal residues of a G_t/i chimera (low intrinsic exchange rate) with corresponding 42 residues of G_s (high intrinsic exchange rate) significantly enhanced the nucleotide exchange rate (22). This same group also reported that disruption of a specific contact between Val³⁰ (N terminus) and Ile³³⁹ (C terminus) alters the rate of GTPS binding, which was inferred as an indirect index of GDP release. Hence, structural interactions between N and C termini of G_t are important to the maintenance of a slow GDP release rate for G_t.

Receptor-mediated GDP release is dependent on the ability of the receptor to interact with the G protein and trigger conformational changes in G that cause release of GDP. Comparing the crystal structure with biochemical data, we can deduce that the receptor contacts G at a site that is more than 20 Å away from the guanine nucleotide binding site (1, 21), thus working at a distance to release GDP. Current theory is that receptor contact with the C terminus of the G-subunit leads to conformational changes that are propagated through G to the GDP binding site (1, 21). However, the requirement for Gß in receptor-G protein interaction and G protein activation suggests that Gß may actively participate in GDP release by opening an exit route for the guanine nucleotide to leave the complex (23). The heterotrimer contains a prominent cavity between G and Gß that is believed to be oriented toward the plasma membrane (7, 24). Activated loops of the receptor might use this cavity to tilt Gß away from G causing the contacts between G and Gß to be disrupted, including contacts near switch I and the ß3-2 loop in G, the potential exit route for the nucleotide. In this way the receptor could use Gß as a lever to release GDP (25). Ala substitutions in Gß at the G-Gß interface near the GDP exit route inhibit receptor-induced GDP/GTP exchange without affecting G-Gß binding (26). Thus, the Gß-dimer is not merely a passive binding partner with the sole purpose of stabilizing G but, rather, Gß actively participates in receptor-mediated G protein activation.

	IV. Structural Determinants of Receptor-G Protein Specificity

Top Abstract I. Introduction II. G Protein Structure III. Molecular Basis for... IV. Structural Determinants of... V. Receptor-Independent... VI. The Receptor-G{alpha}... VII. G{alpha} Interaction with... VIII. Gß{gamma}... IX. Molecular Basis for... X. Regulation of G... XI. Advances for the... References

 
For the purposes of this review, we will limit ourselves to a discussion of regions within G and Gß that have been determined to mediate receptor-G protein specificity. For a thorough review of specific sites on heptahelical receptors, which direct receptor-G protein coupling specificity, the reader is referred to Refs. 27 and 28 for reviews. The extreme C terminus of G (in particular the last five residues) has been established as an important mediator of receptor-G protein interaction (23, 29, 30, 31). For example, ADP ribosylation of residue -4 by pertussis toxin uncouples G_i/G_o proteins from receptors (32). Phosphorylation of a tyrosine residue at -4 in G_q/11 was shown to be required for coupling to metabotropic glutamate receptors (33) although this has not been demonstrated in intact cells. In addition, the requirement of phosphorylation at the tyrosine residue of G_q/11 cannot be generalized as M₁ muscarinic receptors, and thrombin receptors were shown to couple readily to G_q/11 proteins in reconstitution experiments (34, 35). Many examples of mutations in this region that alter receptor-G protein specificity have been also reported (36, 37, 38). In addition, several investigators have generated sequence-specific C-terminal peptides or antibodies targeting the C-terminal domain to study receptor-G protein interaction. Antibodies recognizing G C-terminal domains block receptor-G protein signaling (39). Instead, sequence-specific C-terminal synthetic peptides either stabilize the active agonist-bound form of the receptor mimicking the G protein (40, 41, 42) or serve as competitive inhibitors of receptor-G protein interface (43). Although blocking peptides are commonly interpreted as evidence of a direct receptor-G protein contact site, peptides may also stabilize or disrupt regions of the protein that transmit conformational changes to the guanine nucleotide binding motif and thereby indirectly affect receptor-mediated G protein activation.

The C terminus is not the only region directing receptor-G protein interactions. Several G-subunits possess identical or nearly identical residues within the extreme C-terminal domain yet exhibit differential coupling to receptors. For example, within the last 11 amino acids of G_i1 and G_t, only a single residue is divergent, yet the serotonin_IB receptor fails to couple to G_t and readily couples to G_i. Investigation into the molecular determinants of this specificity indicated that two residues within the 4-helix of G_i1 are critical mediators of this receptor-G protein coupling profile (44, 45). Key residues for coupling specificity have been also identified within the N terminus (36, 39, 46), the 2-helix, and 2-ß4 loop regions (47, 48) as well as within the 4-helix and 4-ß6 loop domain (44, 48, 49). Segments of Gß- and G-subunits may also contribute to the receptor interacting surface of heterotrimers (46, 50, 51, 52, 53). Using a peptide specific for -helical residues in G_s, Krieger-Brauer et al. (54) blocked ß-adrenergic receptor-mediated activation of both G_s- and Gß-effectors. In contrast, a C-terminal sequence-specific peptide for G_s only prevented G_s-mediated effector activation, suggesting that the extreme C terminus of G_s is required for G-mediated signaling but is not critical for ß-adrenergic receptor recognition and dissociation of G from Gß (54). Together, these studies suggest that the relative importance of the C terminus for directing receptor-G protein interactions may be dependent on G and receptor subtypes. Receptor-G protein specificity is clearly not mediated solely by one structural feature of G-subunits but appears to result from a network of specific contacts between the receptor and G protein which differs for each G-subunit and for each receptor and results in a large number of possible combinations that can bring remarkable specificity into a system with only a few central players. As suggested by Blahos et al. (36), one of the difficulties in isolating the specific determinants of receptor-G protein coupling has been that G protein coupling may still occur even when interactions at certain contact points are weak, absent, or negative if these frailties can be overcome by a stronger interaction at other contact points or when regions that may weaken coupling are removed from either the receptor or the G protein.

	V. Receptor-Independent Activators of G Protein Signaling (AGS Proteins)

Top Abstract I. Introduction II. G Protein Structure III. Molecular Basis for... IV. Structural Determinants of... V. Receptor-Independent... VI. The Receptor-G{alpha}... VII. G{alpha} Interaction with... VIII. Gß{gamma}... IX. Molecular Basis for... X. Regulation of G... XI. Advances for the... References

 
A novel class of signaling proteins, termed AGS proteins, has been identified (55, 56). AGS proteins activate heterotrimeric G proteins independently of receptor activation. The mechanism for AGS activation differs among members of this family. AGS1 has been found experimentally to promote GTPS binding. AGS2 selectively associates with Gß, whereas AGS3 binds to G and exhibits a preference for GDP-G vs. GTP-G. AGS3 has been shown to prevent the reassociation of Gß with the G-subunit and function as a guanine dissociation inhibitor for G_i-subunits (57). AGS3 contains a G protein-regulatory motif. This G protein regulatory motif or GoLOCO repeat is an approximately 20-amino acid domain found in several proteins that interact with and/or regulate G proteins, e.g., AGS3, the Partner of Inscuteable and its mammalian homolog, LGN, Purkinje cell protein 2, and Rap1 GTPase-activating protein (GAP). The physiological role of these proteins in vivo remains to be determined, but one possible role for these proteins may be in the regulation of G proteins that do not reside near the plasma membrane and cannot be activated directly by receptors, e.g., G proteins in the Golgi that regulate vesicular trafficking (58). Little is known about the role of this pool of G proteins, and the discovery of AGS proteins may stimulate research into a new dimension of heterotrimeric G protein signaling.

	VI. The Receptor-G Protein Interface as a Therapeutic Target

Top Abstract I. Introduction II. G Protein Structure III. Molecular Basis for... IV. Structural Determinants of... V. Receptor-Independent... VI. The Receptor-G{alpha}... VII. G{alpha} Interaction with... VIII. Gß{gamma}... IX. Molecular Basis for... X. Regulation of G... XI. Advances for the... References

 
Traditionally, the extracellular surface and transmembrane domains of G protein-coupled receptors have served as a target for the development of drugs that can selectively activate or inactivate specific cellular pathways. However, some receptor isoforms, such as the dopamine D_2L and D_2S receptors, and the D₄ receptor variants differ only on the intracellular surface of the protein (59, 60) and cannot be readily distinguished by targeting the ligand-binding site. Moreover, many receptors promiscuously couple to several G protein subtypes in what may be a tissue- or cell-specific phenomenon. Therefore, additional therapeutic targets will certainly be required to more specifically influence intracellular signaling events. One avenue being explored by our laboratory and others is the use of peptide inhibitors that target the receptor-G protein interface (43, 61, 62). Currently, these peptides represent either G C-terminal-specific sequences or peptides isolated from a combinatorial library based on C-terminal G-sequences and screened for high-affinity receptor binding (31). These studies are based on the idea that the C terminus of G-subunits serves as a key receptor contact site and mediator of receptor-G protein specificity. In the short term, these peptides may provide useful tools for exploring specificity of G protein-mediated signaling.

The delivery of peptide inhibitors represents a challenge to the therapeutic use of these tools. Possible delivery systems include the use of inducible retroviral minigene vectors (64), incorporation of peptides into liposomes (65), or the fusion of peptides to a viral peptide sequence that carries the C-terminal peptide into the cell (66). Alternatively, peptidomimetics may prove to be more stable and bioavailable. Selective targeting to specific organs is likely to prove beneficial, because Akhter et al. (67) have demonstrated that transgenic mice selectively expressing a Gq C-terminal minigene in the myocardium exhibit a marked inhibition of _1B-adrenergic receptor-mediated inositol phosphate production and blockade of cardiac hypertrophy. The identification of peptide inhibitors with high affinity for specific receptor subtypes and/or variants would also allow for more selective inhibition of signaling pathways. Despite the significant hurdles, targeting the receptor-G protein interface will clarify the complex coordination of players in signaling cascades and may prove therapeutically useful in the future.

	VII. G Interaction with Effectors

Top Abstract I. Introduction II. G Protein Structure III. Molecular Basis for... IV. Structural Determinants of... V. Receptor-Independent... VI. The Receptor-G{alpha}... VII. G{alpha} Interaction with... VIII. Gß{gamma}... IX. Molecular Basis for... X. Regulation of G... XI. Advances for the... References

 
Once G-GTP has dissociated from the Gß-dimer, G can directly interact with effector proteins to continue the signaling cascade. The specific effector proteins activated by G are dependent on the G-subtype and are summarized in Table 1. Well-defined G effectors, such as adenylyl cyclase (AC) and phospholipase C (PLC), have been the topic of several excellent reviews (68, 69).

Overall, several patterns emerge upon examination of the G-effectors. First, each G-family activates a distinct profile of effectors. The molecular basis for this divergence has not been completely elucidated. Cocrystallization studies of G_s and the catalytic domains of AC have identified specific contacts within G_s at the 2-helix (SII) and the 3-ß5 loop (70). In addition, the 4-ß6 loop of G_s also plays a role in AC activation (71). Sunahara et al. (72) demonstrated that GDP-bound G_s can also stimulate AC, albeit with a lower potency than the GTP-bound -subunit. These data are intriguing because they suggest that reassociation of G with Gß is required for the complete termination of G_s signaling, and inhibition of reassociation could prolong both G- and Gß-mediated signaling. In addition, Gß could serve to prolong signaling because it can block the PLCß-mediated acceleration of GTPase activity at G_q-proteins (73). Second, within a family, each G-subunit exhibits a differential profile of effector activation. For example, G_i2 is required to inhibit forskolin-stimulated AC activity whereas G_i3 serves to inhibit G_s-activated AC (74). In addition, ₁-adrenergic receptors elevate intracellular Ca²⁺ by two distinct mechanisms that are dependent on the G-subunit coupled to the receptor: G_q releases Ca²⁺ from the endoplasmic reticulum whereas G₁₁ activates a nonselective cation channel (75). Third, some G-subunits have only one identified effector, such as cGMP phosphodiesterase for G_t whereas others more promiscuously couple to several effector proteins. Lastly, effectors for some G-subunits have yet to be definitively identified, and the search for novel G-effectors is a rapidly growing area of research. A number of proteins that directly interact with G-subunits have been identified, yet further evidence awaits as to whether guanine nucleotide binding to G regulates the activity of these proteins in vivo in response to receptor activation. Nonetheless, some of the most recent studies identifying novel putative G-effectors are discussed below.

Using a yeast-two-hybrid screen, Jordan et al. (76) identified direct interactions between G_o and Rap1 GAP, Gz GAP, and RGS17. This group also determined that Rap1 GAP interacts with G_i-proteins but not with G_q or G_s. However, receptor-mediated activation of these proteins was not demonstrated. Interestingly, Rap1 GAP interacted preferentially with GDP-bound G_o, suggesting that G_o-GDP may sequester Rap1 GAP away from Rap1, resulting in a sustained activation of MAPK. These findings reveal a novel mechanism of G protein function that is dependent on GDP-liganded G proteins. Gß-subunits might then be considered as inhibitors of G-GDP proteins (and vice versa).

In search of G_z-effectors, Chen et al. (77) screened a cDNA expression library using phosphorylated G_z-GTPS as a probe. This group identified two proteins that interact with G_z and named them GRIN1 and GRIN2 for G protein-regulated inducer of neurite outgrowth 1 and 2. Both GRIN1 and GRIN2 bound to activated G proteins (G_o, G_i, and G_z) and were identified in neural tissue, but the regulatory mechanism for neurite growth is unknown.

The Ca²⁺ binding protein calnuc (nucleobindin) is a potential effector for G_i3 and G_s (78, 79). The binding of calnuc to G_i3 has been shown to be Ca²⁺ and Mg²⁺ dependent (80). This ion dependence has not been shown explicitly for G_s, probably because calnuc undergoes a conformational change after Ca²⁺ binding (81) that could be necessary for G protein interaction.

Bruton’s tyrosine kinase (Btk) has been identified as a novel effector for G_q proteins because G_q activates Btk both in vitro and in vivo, and this activation is required for receptor-mediated stimulation of p38 MAPK (82). However, the generalization of these results to other G_q family members remains to be determined.

Although a role for G_12/13-proteins had been established in several physiological events such as stress fiber formation, cellular transformation, regulation of Na⁺/H⁺ exchange, modulation of inducible nitric oxide synthase expression, and regulation of Erk and c-jun kinase activity (83), direct interaction of G_12/13 with effector proteins has been established recently, when Hart et al. (84) identified p115RhoGEF as a direct effector for G₁₃. A RGS protein, p115RhoGEF, is also shown to serve as a GAP for both G₁₂ and G₁₃. However, only activated G₁₃ is able to stimulate p115RhoGEF to trigger GDP/GTP exchange on the small molecular weight G protein Rho. In addition, the cytoskeletal-associated protein radixin has been found to interact with G₁₃ (85) whereas an interaction between G₁₂ and heatshock protein 90 is required for G₁₂-induced serum response element activation, cytoskeletal changes, and mitogenic response (86).

	VIII. Gß Interaction with Effectors

Top Abstract I. Introduction II. G Protein Structure III. Molecular Basis for... IV. Structural Determinants of... V. Receptor-Independent... VI. The Receptor-G{alpha}... VII. G{alpha} Interaction with... VIII. Gß{gamma}... IX. Molecular Basis for... X. Regulation of G... XI. Advances for the... References

 
Initially, Gß was thought to facilitate the completion of intracellular information transfer passively by binding to G and hastening the return of the heterotrimer to the plasma membrane, thereby preventing noise or spontaneous G activation in the absence of receptor stimulation (87). This belief changed when Gß was shown to activate a K⁺-selective ion channel (I_KACh) in cardiac atrial cells (88). Today, Gß is known to interact with and activate several effectors, including PLCß2 and ß3 (89, 90), ACs (91), ß-adrenergic receptor kinase (92), phosphoinositide 3-kinase (PI₃ kinase) (93, 94), components of the MAPK cascade (95), and K⁺ and Ca²⁺ channels (88, 96, 97, 98) (Table 2). As the list of Gß-effectors continues to grow, recent attention has turned toward examining the mechanisms responsible for Gß-specific signaling.

View this table: [in this window] [in a new window]   TABLE 2. Effectors regulated by Gß dimers

A. Gß-Dimer composition directs effector and receptor coupling
What is the physiological significance of the formation of different Gß-dimers? Although it was previously thought that Gß-dimers were for the most part interchangeable, current research indicates that Gß-dimer composition determines the quality and efficiency of effector activation and may mediate receptor-G protein coupling specificity similar to G-subunits. For example, when nine unique dimers of Gß₁ or Gß₂ with G_{(1, 2, 3, 5 or 7)} were tested for the ability to activate various PLCß isoforms, all dimers could activate the various PLCß isoforms except retinal-specific Gß₁₁ (111, 112). Likewise, Gß₁₁ was markedly less effective at stimulation of ACII and inhibition of ACI than other Gß dimer combinations (111, 112). A comparison of Gß₁₂ with Gß₅₂ demonstrated that Gß₅₂ is a much weaker inhibitor of ACI, ACV, and ACVI. In addition, Gß₁₂ stimulated ACII activity, whereas Gß₅₂ inhibited the activity of this enzyme (113). In contrast, both Gß₁₂ and Gß₅₂ activated PLCß₂ with similar potency and efficacy (114). Finally, the rank order for Gß-subtype inhibition of voltage-dependent N-type Ca²⁺ currents differs from enzyme activation [Gß₁ = Gß₂ > Gß₅>>Gß₃ = Gß₄; (115)], and this potency difference may be related to the ability of the various Gß-subunits to physically interact with the L_I-II loop of the Ca²⁺ channel (115). Together, these data demonstrate that the primary sequence of the Gß-subunit is a major determinant of effector coupling efficiency and specificity. Isolation of the structural features responsible for effector variation remains to be completely determined. Recently, Mirshahi et al. (116) have shown that Ser⁶⁷ in Gß₁ is part of a functional domain that regulates several different effectors whereas other residues of the ß-propeller seem to direct the effector specificity.

With respect to receptor-G protein coupling specificity, both Gß₁₂ and Gß₅₂ can couple G_q-proteins to endothelin B and M₁ muscarinic receptors. However, Gß₁₂ but not Gß₅₂ promotes endothelin B receptor-G_i-protein interaction (107). Thus, the Gß₅₂-dimer specifically couples G_q-proteins to receptors (117). With the exception of Gß₅, the identity of the Gß-subunit does not currently appear to be a critical determinant of receptor-G protein specificity. For example, A₁ adenosine receptors couple equally well to G_i-proteins containing Gß₁₂-, Gß₁₃-, Gß₂₂-, or Gß₂₃-dimers as measured by reconstitution of high-affinity agonist binding (118). In contrast, G proteins containing a farnesylated -subunit coupled less efficiently to the A₁ receptor, suggesting that lipid modification of the Gß-dimer can influence receptor-G protein coupling efficiency (52).

B. Structural determinants of effector specificity
Unlike G-subunits, the conformation of Gß-dimers does not significantly change whether Gß is in the inactive heterotrimeric complex or in the free active state. One notable exception to this idea is that phosducin binding to Gß induces a conformational change primarily in blades 1 and 7, thus preventing Gß association with additional effectors (119). Once dissociated from G, Gß can interact with a number of effectors. Using alanine scanning mutagenesis, our laboratory (26) and others (120, 121) previously identified residues on Gß that contact G and that mediate a number of effector interactions including ion channels, PLCß₂, and ACII (Fig. 2C). Regions important for ACII interaction map roughly to blades 2, 3, and 5, whereas the N-terminal interface of Gß interacts with G protein-activated, inwardly rectifying potassium channels, 1 and 4 (26). In addition, point mutations either on the G interacting face of blades 1–4 or mutations in the outer loops of blades 2, 6, and 7 inhibit PLCß₂ activity (26, 120); whereas, PLCß₃ is inhibited by point mutations within blades 2 and 5 (121). Therefore, each effector contacts a unique but overlapping set of residues on Gß, and some of these sites also represent G interacting sites. These studies are consistent with the idea that interaction with precludes Gß binding to effector proteins. Mutational studies continue to reveal the molecular basis for effector interaction as well as the structural basis for variations between Gß-subunits in effector coupling efficiency. However, one key question yet to be resolved is how Gß activates a particular effector once freed from G, in a cytoplasmic milieu full of potential partners. Signaling specificity could be brought about by factors such as discrete subcellular localization of effectors, compartmentalization of scaffolding components, and cell type-specific expression of signaling molecules (122). The formation of signaling networks that bring together specific receptors, G proteins, regulatory proteins, enzymes, and substrates is a hot area of research and will likely reveal key factors regulating signaling specificity.

C. Novel Gß-effectors
At the current discovery rate of Gß-effectors, the final tally of proteins that interact with the Gß-dimer is likely to exceed that for G-subunits (68). As shown in Tables 1 and 2, Gß- and G-subunits interact with a number of common effectors, such as PLCß, Bruton’s tyrosine kinase, and certain types of ACs. These effector interactions can be independent, synergistic, or antagonistic. For example, Gß-subunits potentiate ACII activation by G_s, but inhibit G_s-stimulated ACI activity. In addition, Gß-dimers interact with a number of novel effectors that are not regulated by G-subunits. These novel effector interactions expand the role of G proteins in the regulation of various cellular processes and are briefly discussed below.

Putative Gß-effectors recently identified include protein kinase D (123), PI₃ kinase (93, 94), tubulin (124), KSR-1 (125), dynamin I (126), Raf-1 protein kinase (127), Tsk protein kinase (128), and calmodulin (129) (see Table 2 and references therein). Although previous data suggest that Gß-effectors bind to an overlapping domain on Gß-subunits, additional studies also indicate that Gß binding to one particular effector does not necessarily preclude Gß interaction with a second effector protein. For instance, Gß binding to calmodulin does not prevent Gß-mediated stimulation of PLCß (129). The ability of Gß to simultaneously regulate different effectors suggests that the Gß conformation is not disturbed upon effector binding. One notable exception to this idea is that phosducin binding to Gß induces a conformational change primarily in blades 1 and 7 preventing Gß association with additional effectors (119). Likewise, Gß interaction with the protein kinase KSR-1 prevents Gß-mediated stimulation of MAPK (125). However, the mechanism responsible for this exclusivity remains to be elucidated. As mentioned before, Chidiac and Ross (73) showed that Gß could prevent the acceleration of the GTPase activity of G_q by PLCß, which implies a dual role for Gß because it can stimulate PLCß activity directly and indirectly (through prolonged activation of G_q).

Although most Gß-effectors are believed to directly interact with the Gß-subunit, a role for the G-subunit has also been suggested. Using a yeast-two-hybrid screen with the protein kinase KSR-1, Bell et al. (125) identified G₂, G₃, and G₁₀ as interacting proteins. The C terminus of G-subunit seems to play a direct role in modulating PLCß functions (130). To date, no specific Gß or G binding domain has been identified, although an intriguing number of Gß interacting proteins contain pleckstrin homology domains. Future research is likely to identify an increasing number of Gß-effector proteins. Recently, our laboratory found that the receptor for activated C kinase 1 and the dynein intermediate chain interact with the Gß₁₁-dimer (131). Gß can inhibit neurotransmitter release independently of second messenger formation and ion channel modulation, perhaps by direct interaction with the exocytotic fusion machinery, because both syntaxin 1B and SNAP25B are Gß binding partners (132).

D. Additional role for Gß₅
Gß_1–4 share 80%–90% sequence homology and are ubiquitously expressed (133). In contrast, Gß₅ shares only about 50% identity with the others and is preferentially expressed in the central nervous system (134). Gß_1–4 are entirely particulate proteins, whereas Gß₅ can exist both in the soluble and membrane fractions (134), and the N-terminal domain of Gß₅ is significantly longer than the other Gß-subunits. Although this region is important for G interaction (135), Gß₅ can dimerize with G, form functional heterotrimers with G, and interact with a number of effectors in response to receptor activation (102, 113, 114, 117, 134). However, unlike other Gß-subunits, Gß₅ can readily dissociate from G under low-stringency conditions and is stable in solution without being complexed to G (136, 137). Free Gß₅ has been shown to interact with certain GAPs known as regulators of G protein signaling (RGS proteins) through a G protein G-subunit-like domain (138, 139). The G protein G-subunit-like domain is a 64-amino acid region (34% identical to G₅) that is present in RGS6, RGS7, RGS9, RGS11, and the Caenorhabditis elegans RGS protein EGL-10 (140). Gß₅ binding to RGS proteins enhances the ability of the proteins to accelerate the GTPase activity of G-subunits (141). In addition, Gß₅ binding to RGS6, -7, and -11 allows for the selective inactivation of G_o (140) and may localize these RGS proteins within the cytosolic compartment (142). Is Gß₅ always associated with an RGS protein in vivo, or does it shuttle between RGS proteins and G-subunits? In native preparations, RGS9 exists in a tight complex with the long splice variant of Gß₅ (Gß_5Long) in vertebrate photoreceptors (138). The Gß_5L-variant was absent from the retinal tissue of RGS9-deficient mice despite the presence of normal levels of Gß₅ mRNA (143). In contrast, Gß_5Short protein levels were normal in knockout mice. Therefore, RGS9 may be required for the translation or stability of Gß_5L in photoreceptor cells whereas Gß_5S may be free to interact with G-subunits (143). Other questions yet to be resolved include: does Gß₅ interact with other proteins outside the RGS family? Do free G-subunits have a signaling role on their own? What is the brain-specific role for Gß₅? The discovery of Gß₅ independent of G has clearly disproved the previous dogma that Gß-subunits associate only with G, and that only through this association do they elicit a physiological response.

	IX. Molecular Basis for G Protein Inactivation

Top Abstract I. Introduction II. G Protein Structure III. Molecular Basis for... IV. Structural Determinants of... V. Receptor-Independent... VI. The Receptor-G{alpha}... VII. G{alpha} Interaction with... VIII. Gß{gamma}... IX. Molecular Basis for... X. Regulation of G... XI. Advances for the... References

 
A. Intrinsic GTPase activity
As previously mentioned, the duration of G protein-mediated effector activation is dependent on the intrinsic GTPase activity of the G-subunit. Like the intrinsic GDP release rates, intrinsic GTP hydrolysis activity varies among G-subunits (83). For example, the catalytic rate constant value for GTP hydrolysis for G_z is approximately 200-fold lower than that of G_s and G_o (83, 144, 145). The GTPase domain is highly homologous among G-subunits and the side chain of a conserved arginine residue (Arg¹⁷⁴ in G_t; located within the helical domain) forms hydrogen bonds with oxygens of the - and -phosphates and the ß- phosphate bridging oxygen. This Arg residue plays a key role in GTP hydrolysis. Thus, mutations of either this Arg or residues contacting it have been reported to alter the GTPase activity of G-subunits (2, 146). Because of the conserved nature of the GTPase domain of G-subunits, the determinants of G-hydrolysis variability are likely to lie in the divergent helical domain and within the N and C termini or be the result of subtle flexibility and conformational changes among G-subunits. The mechanisms responsible for variations in GTP hydrolysis rates have not been studied in detail. Research in this area has focused instead on identifying proteins that directly interact with G-subunits to regulate their intrinsic GTPase activity. Some of these key studies are discussed below. For the interested reader, detailed descriptions of the mechanism of GTP hydrolysis can be found elsewhere (2, 9).

B. G Interaction with GTPase-activating proteins (GAPs)
Several years ago, researchers noted that the intrinsic GTPase activity of G-subunits occurs in vitro at a much slower rate than can account for the observed deactivation rates of G protein-controlled processes (147, 148). Therefore, speculation mounted that, in vivo, an additional protein was rapidly terminating signal transduction, returning the system to an agonist-responsive state. In mammals, the G-effectors PLCß and the -subunit of phosphodiesterase (P) were two of the earliest identified GAPs for G_q and G_t, respectively (149, 150, 151). Most recently, Scholich et al. (152) have determined that the effector ACV serves as a GAP for G_s. Thus, after activation by G, an effector can feed back on the activated G-subunit and significantly reduce the duration and amplitude of the signal generated.

In addition to effector-mediated feedback inhibition, RGS proteins enhance the GTPase activity of G-subunits, thereby reducing the duration and amplitude of both G- and Gß-mediated cellular responses (153, 154, 155, 156). RGS proteins share a common approximately 125-amino acid domain termed the RGS box (157, 158). To date, more than 30 mammalian RGS proteins have been identified (156, 158, 159, 160), each containing 23 conserved hydrophobic residues at the core of the RGS domain (155, 156, 159, 161). In vitro, the RGS core domain is both necessary and sufficient for GAP activity. However, in vivo this is not the case. Our laboratory and others (162, 163) have demonstrated that in native retinal preparations, RGS9 requires effector activation for the full expression of RGS GAP activity. Likewise, the core RGS domain of RGS16 can stimulate G_o GTP hydrolysis in vitro but requires additional N-terminal residues for functional activity in vivo (164). These studies suggest that in vivo the noncatalytic domains regulate RGS GAP activity through interactions with cellular factors. Only two such factors have been identified to date, Gß₅ and phosphodiesterase E (141, 151, 165). Noncatalytic domains of RGS proteins have also been suggested to mediate signal transduction pathway specificity and subcellular targeting of RGS proteins (154, 166).

GAPs for heterotrimeric G proteins accelerate GTP hydrolysis in a manner that differs from that observed with monomeric G protein GAPs. For example, Ras GAP inserts a catalytic Arg residue into the active site that participates in the hydrolysis step (2). However, this Arg finger is provided by the helical domain in heterotrimeric G proteins and mediates intrinsic GTP hydrolysis as discussed above (2). In contrast, RGS proteins bind to the switch regions on G and thereby stabilize the G transition state toward GTP hydrolysis (167). The mechanism for effector-mediated GAP activity has not been clearly delineated. By analogy, effector-mediated GAP activity may also occur through a similar stabilizing mechanism. However, differences in activity between effector GAPs and RGS GAPs have been observed. For example, Mukhopadhyay and Ross (168) demonstrated that RGS4 produces a 2-fold greater acceleration of the G_q-bound GTP hydrolysis rate in comparison to PLCß, but PLCß is 100 times more potent than RGS4. Although these findings might suggest different mechanisms of GAP activity for effectors and RGS GAPs, Gß can inhibit the GAP activity of both PLCß₁ and RGS4 (73). This is consistent with the idea that Gß, effectors, and RGS proteins bind to the same region on G, namely the switch regions of the GTPase domain. Thus, RGS proteins can act as effector inhibitors as well as GAPs. On the other hand, we and others recently determined that the effector P enhances the GAP activity of the regulator of G protein signaling 9 (RGS9) core domain by increasing the affinity of the RGS9 domain for a G_t/i chimera (163, 170). These studies suggest that RGS proteins may be regulated through their participation in a signal transduction complex that may include receptors and effectors and may be localized near the plasma membrane. A similar suggestion was proposed by Chidiac and Ross (73). Our laboratory has also determined that the -helical domain of G_t (a G_i family member) is a key molecular determinant of the selectivity that the RGS9 core displays as a GAP for G_t vs. G_i (163). Therefore, RGS protein affinity and GAP activity for various G-subunits may be mediated, at least in part, by the primary structure of the G-subunit as well as by the sequence of the RGS box. Further in-depth discussion of RGS proteins can be found in one of several reviews on this topic (154, 155, 156, 161, 166).

	X. Regulation of G Protein Function by Covalent Modification

Top Abstract I. Introduction II. G Protein Structure III. Molecular Basis for... IV. Structural Determinants of... V. Receptor-Independent... VI. The Receptor-G{alpha}... VII. G{alpha} Interaction with... VIII. Gß{gamma}... IX. Molecular Basis for... X. Regulation of G... XI. Advances for the... References

 
G protein signaling cascades are also regulated by posttranslational modification of the G proteins themselves, which includes phosphorylation and/or acylation of G- and Gß-subunits. Phosphorylation of G-subunits by protein kinase C inhibits signal transduction through G_i family members (171, 172, 173, 174). For G_z, stoichiometric phosphorylation occurs at N-terminal Ser¹⁶ and G_z-GDP is the preferred substrate (175, 176). Protein kinase C phosphorylation of G_z prevents heterotrimer formation (175) and inhibits GAP activity of RGSZ1 (177). Thus, phosphorylation could significantly prolong Gß-effector activation while reducing G-effector stimulation. The GDP-bound forms of G_t and G_s are also kinase substrates (178, 179), and phosphorylation of G₁₂ prevents interaction with Gß (180). Phosphorylation of Gß- (181) and G-subunits has also been reported (182), and phosphorylation of Gß₁₁₂ inhibits Gß-mediated AC activation without altering the activation of PLCß (183). Thus, phosphorylation cannot only dissociate G- and Gß-mediated signaling, but it also regulates the selective modulation of particular Gß-effectors.

A. G protein lipidation
In addition to phosphorylation, G-subunits are lipidated (myristoylated and palmitoylated) at their N termini. N-myristoylation results from cotranslational addition of the saturated 14-carbon fatty acid myristate to a Gly residue at the second position after the removal of the initiating Met by the enzyme methionine amino-peptidase (184). A stable amide bond links the myristate to the protein. Hence, this myristoylation is essentially an irreversible modification. Only G-subunits of G_i family are myristoylated (see Refs. 174 and 185, 186, 187 for review). In addition, all G protein G-subunits, except G_t, contain the posttranslationally attached saturated 16-carbon fatty acid palmitate and some G-subunits (G_q, G₁₁, G₁₃, and G₁₆) are palmitoylated at multiple sites (see Refs. 174 , 188 , and 189 for review). Palmitoylation of proteins results from the esterification of Cys thiol groups by palmitate. Due to its unstable character, palmitoylation is readily reversible and subject to regulation (188, 190). As yet, palmitoylation cannot be accurately predicted based on primary sequence. However, palmitoylation occurs frequently in proximity to other lipid modifications such as myristoylation or prenylation.

The G-subunit when dimerized with Gß is isoprenylated posttranslationally. The 15-carbon isoprenoid farnesyl (G₁, G₈, and G₁₁) or the 20-carbon isoprenoid geranylgeranyl (other G-subunits) is attached via a stable thioether bond to a Cys residue located in the C-terminal CAAX box of G, followed by the proteolytic removal of the C-terminal three amino acids and then the carboxyl methylation of the new C terminus (191). The X residue in the CAAX motif is a major determinant of the isoprenyl group. If X is a Ser, Met, Gln, or Ala, the proteins are farnesylated, whereas Leu at this position results in geranylgeranylation (see Ref. 192 for review). Carboxymethylation of the C terminus of G appears to modulate the affinity of the membrane attachment (193).

B. The role of lipid modifications in G protein membrane association and consequent signaling functions
One clear function of fatty acid acylation is to serve as a hydrophobic membrane anchor. For the G_i family of G-subunits that are both myristoylated and palmitoylated, both modifications contribute to the membrane association. Removal of the palmitoylation site while preserving myristoylation results in a partial shift in localization from the membrane to the cytoplasm (194, 195, 196, 197). Likewise, mutation of the N-terminal Gly on G, which abolishes myristoylation, also inhibits palmitoylation and similarly shifts protein localization (184, 198, 199). Shahinian and Silvius (200) have recently proposed a "kinetic membrane trapping" model for G proteins to account for this localization dependence on both lipid modifications. Within this two-signal model of membrane binding, myristoylation and palmitoylation cooperate to target G_i-subunits to the plasma membrane. Myristoylation serves as the initial signal bringing the protein to the membrane, and palmitoylation is the second signal that further secures this interaction. In addition, palmitoylation may specifically target G proteins to the plasma membrane rather than to intracellular organelle membranes (174, 195, 201). Consistent with this two-signal model, in the case of myristoylation-defective mutants of G_z and G_o, the prenylated Gß-subunit can substitute for myristoylation and carry the -subunit to the plasma membrane where it can be palmitoylated and fulfill its signaling activity (174, 202).

For G-subunits that are modified solely by palmitate (G_s, G_q, G₁₂, and G₁₃), mutations that prevent palmitoylation markedly impair membrane association (203, 204, 205, 206). In addition, Gß appears to be a crucial prerequisite for membrane anchoring and palmitoylation of G_s and G_q (207). However, by enzymatically depalmitoylating G_q, Hepler et al. (208) have determined that Cys residues rather than palmitoylation per se are critical determinants of G_q-mediated signal transduction. Because most studies investigating the role of palmitoylation have relied on mutating Cys residues, further studies are needed to determine whether the significance of palmitoylation itself has been overestimated thus far. Indeed, a paper by Fishburn et al. (209) used a mutant Gß complex, which mislocalized to the mitochondrial membrane, to investigate the relative contributions of protein-protein interactions vs. lipid modifications in controlling membrane targeting of G_z. Using this approach, these authors determined that G_z interaction with Gß, rather than palmitate, directs specific targeting of G protein G-subunits to membranes.

Lipid modifications also regulate protein-protein interactions. For example, N-myristoylation of G modulates Gß (210) and effector interactions (211), and palmitoylation increases the affinity of G_s for Gß (212). In addition, palmitoylated G_sß is more resistant to thioesterase cleavage of palmitate than free palmitoylated G_s (212). Palmitoylation can also inhibit the interaction of GzGAP (an RGS protein) with G_z (213). Thus, the palmitoylation state of G proteins can affect their ability to serve as signaling molecules. As part of a feedback mechanism, palmitate turnover can also be regulated by receptor activity (196, 214).

The addition of the prenyl group to the G-subunit plays a central role in the membrane association of the Gß complex (for review see Ref. 215). Although not required for Gß-dimer formation, isoprenylation of G is necessary for productive interaction of Gß with other proteins including G (111) and effectors such as AC (216, 217, 218), PLC (217, 218), and PI₃ kinase (217, 219, 220) as well as with receptors (52).

	XI. Advances for the Future: Investigating the Dynamic Nature of G Protein Signaling

Top Abstract I. Introduction II. G Protein Structure III. Molecular Basis for... IV. Structural Determinants of... V. Receptor-Independent... VI. The Receptor-G{alpha}... VII. G{alpha} Interaction with... VIII. Gß{gamma}... IX. Molecular Basis for... X. Regulation of G... XI. Advances for the... References

 
The resolution of crystal structures for active, inactive, transition state of G (3, 4, 5, 6) has provided a basis for understanding G proteins as molecular switches for signaling pathways. These studies also provide a framework for conducting structural, functional, and biochemical experiments that can extend our understanding of G proteins along with their various signaling partners. Because only a few G proteins have been crystallized to date (see Table 3), interpretations and conclusions from these structures may not reflect the full complexity of subunit combinations. Moreover, the static nature of such structures may actually limit our understanding of the dynamic nature of G protein signaling. To more accurately assess G protein interactions with receptors, effectors, and regulators of G protein signaling, it will be necessary to take advantage of new techniques that can provide insights into the complex nature of G protein activation. A few of these techniques are described below.

Spin labeling can also be used to examine changes in protein conformation in real time. This technique requires introduction of a nitroxide side chain at specific residues and electron paramagnetic resonance signal from the nitroxide spin label can detect and report subtle changes in its local environment. It is possible to determine changes in solvent accessibility, dynamics, and intermolecular distances of side chains in solution in real time, yielding information about the time scale and magnitude of structural changes in the labeled region of the protein. Spin pairs can be used to determine changes in the secondary structure of proteins; introduction of spin labels at positions (i) and (i + 4) allows examination of helical structure within proteins. Changes can be measured on a millisecond time scale. Farrens et al. (224) successfully employed this technique to determine movements of helices that accompany rhodopsin activation. They found that -helix C of rhodopsin moves as a rigid unit in relation to -helix F upon light activation of this receptor. This technique is being further used in studies to determine conformational changes in the N terminus of G_i upon activation, because these residues are absent or disordered in most high-resolution crystal structures of GDP- or GTPS-bound form of G-subunits (3, 4, 6) (see Table 3) with the exception of the G_i/RGS4 complex. In the crystal structure of RGS4 core domain bound to aluminum fluoride-activated G_i-GDP subunits, G_i makes two differing sets of contacts with the RGS molecule. One contact is through the G_i-switch region binding to the RGS core domain, whereas the second contact is through the N terminus of the G_i binding to an adjacent RGS molecule in the crystal. This suggests some type of crystallization artifact, leaving a question as to the relevance of the N terminus present in this 2.8-Å structure. Although it is clear from heterotrimeric structures that Gß binding stabilizes an N-terminal -helix in G-subunits, this may change upon activation. Indeed, site-directed spin-labeling studies have shown that G_i N terminus is dynamically disordered in the GDP-bound form, but adopts a structure consistent with an -helix upon interaction with Gß (225). However, activation of the spin-labeled G_iß complex by photoisomerized rhodopsin in the presence of GTPS causes the N-terminal domain of G_i to revert to a dynamically disordered state similar to that of the GDP-bound form (225).

Another powerful technique for measuring protein-protein interactions in real time is surface plasmon resonance. This technique measures changes in refractive index on the surface of a chemically modified sensor chip as a binding event occurs. The resultant binding curve allows for a quantitative measure of affinity of the binding interaction. Figler et al. (226) used this technique to determine the affinities of G-subunits for various Gß combinations. Current advances include development of methods to immobilize vesicles to a sensor chip derivatized with lipophilic alkyl chains, thus anchoring intact vesicles and providing a physical and chemical environment similar to that of cell membranes, which can be used to measure protein-protein interactions of membrane-associated proteins (227).

Computational approaches such as structure prediction and three-dimensional modeling and mathematical techniques such as monte-carlo simulations all provide valuable insights into G protein signaling. More importantly, they are valuable tools that serve to direct further biochemical and functional experiments. These approaches, combined with genetics, can be used to define and examine key components of the signaling pathway, which will both broaden our understanding of the complex nature of G protein signaling and lead to new questions for further investigations.

Structural and functional aspects of heterotrimeric G proteins, their binding partners, and the signaling networks in which they participate are the subjects of intense investigation, and dramatic progress has been made in recent years. The next frontier is to understand how signaling pathways interact with each other to form signaling networks (241). Cells are bombarded with a multiplicity of ligands, and the cellular response is somehow integrated based on all its responses. The experimental approaches to this problem are beginning to be available, but are in their infancy. Certainly, many new approaches to these issues of complexity in cellular signaling will need to be pioneered, and will surely lead to new insights.

	Acknowledgments

 
We apologize to all whose work could not be recognized because of page restrictions. We are grateful to Ms. Simona Ioffe and Ms. Anjela Papassavas for their assistance in gathering information for this review.

	Footnotes

 
Abbreviations: AC, Adenylyl cyclase; AGS, activators of G protein signaling; GAP, GTPase-activating protein; GRIN, G protein-regulated inducer of neurite outgrowth; PI₃ kinase, phosphoinositide 3-kinase; PLC, phospholipase C; RGS, regulator of G protein signaling.

	References

Top Abstract I. Introduction II. G Protein Structure III. Molecular Basis for... IV. Structural Determinants of... V. Receptor-Independent... VI. The Receptor-G{alpha}... VII. G{alpha} Interaction with... VIII. Gß{gamma}... IX. Molecular Basis for... X. Regulation of G... XI. Advances for the... References

 

1. Hamm HE 1998 The many faces of G protein signaling. J Biol Chem 273:669–672[Free Full Text]
2. Sprang SR 1997 G protein mechanisms: insights from structural analysis. Annu Rev Biochem 66:639–678[CrossRef][Medline]
3. Noel JP, Hamm HE, Sigler PB 1993 The 2. 2 Å crystal structure of transducin- complexed with GTPS. Nature 366:654–663[CrossRef][Medline]
4. Lambright DG, Noel JP, Hamm HE, Sigler PB 1994 Structural determinants for activation of the -subunit of a heterotrimeric G protein. Nature 369:621–628[CrossRef][Medline]
5. Sondek J, Lambright DG, Noel JP, Hamm HE, Sigler PB 1994 GTPase mechanism of G proteins from the 1.7 Å crystal structure of transducin ^.GDP^.AIF₄^-. Nature 372:276–279[CrossRef][Medline]
6. Coleman DE, Berghuis AM, Lee E, Linder ME, Gilman AG, Sprang SR 1994 Structures of active conformations of Gi1 and the mechanism of GTP hydrolysis. Science 265:1405–1412[Abstract/Free Full Text]
7. Lambright DG, Sondek J, Bohm A, Skiba NP, Hamm HE, Sigler PB 1996 The 2.0 Å crystal structure of a heterotrimeric G protein. Nature 379:311–319[CrossRef][Medline]
8. Wall MA, Coleman DE, Lee E, Iniguez-Lluhi JA, Posner BA, Gilman AG, Sprang SR 1995 The structure of the G protein heterotrimer Gi1ß12. Cell 83:1047–1058[CrossRef][Medline]
9. Rens-Domiano S, Hamm HE 1995 Structural and functional relationship of heterotrimeric G-proteins. FASEB J 9:1059–1066[Abstract]
10. Downes GB, Gautam N 1999 The G protein subunit gene families. Genomics 62:544–552[CrossRef][Medline]
11. Denker BM, Boutin PM, Neer EJ 1995 Interactions between the amino- and carboxyl-terminal regions of G subunits: analysis of mutated Go/G i2 chimeras. Biochemistry 34:5544–5553[CrossRef][Medline]
12. Higashijima T, Ferguson KM, Smigel MD, Gilman AG 1987 The effect of GTP and Mg²⁺ on the GTPase activity and the fluorescent properties of Go. J Biol Chem 26:757–761
13. Stryer L 1986 Cyclic GMP cascade of vision. Annu Rev Neurosci 9:87–119[CrossRef][Medline]
14. Iiri T, Herzmark P, Nakamoto JM, van Dop C, Bourne HR 1994 Rapid GDP release from Gs in patients with gain and loss of endocrine function. Nature 371:164–168[CrossRef][Medline]
15. Posner BA, Mixon MB, Wall MA, Sprang SR, Gilman AG 1998 The A326S mutant of Gi1 as an approximation of the receptor-bound state. J Biol Chem 273:21752–21758[Abstract/Free Full Text]
16. Thomas TC, Schmidt CJ, Neer EJ 1993 G-protein o subunit: mutation of conserved cysteines identifies a subunit contact surface and alters GDP affinity. Proc Natl Acad Sci USA 90:10295–10298[Abstract/Free Full Text]
17. Marin EP, Krishna AG, Sakmar TP 2001 Rapid activation of transducin by mutations distant from the nucleotide-binding site: evidence for a mechanistic model of receptor-catalyzed nucleotide exchange by G proteins. J Biol Chem 276:27400–27405[Abstract/Free Full Text]
18. Echeverria V, Hinrichs MV, Torrejon M, Ropero S, Martinez J, Toro MJ, Olate J 2000 Mutagenesis in the switch IV of the helical domain of the human Gs reduces its GDP/GTP exchange rate. J Cell Biochem 76:368–375[CrossRef][Medline]
19. Remmers AE, Engel C, Liu M, Neubig RR 1999 Interdomain interactions regulate GDP release from heterotrimeric G proteins. Biochemistry 38:13795–13800[CrossRef][Medline]
20. Grishina G, Berlot CH 1998 Mutations at the domain interface of Gs impair receptor-mediated activation by altering receptor and guanine nucleotide binding. J Biol Chem 273:15053–15060[Abstract/Free Full Text]
21. Yang C-S, Skiba NP, Mazzoni MR, Hamm HE 1999 Conformational changes at the carboxyl terminus of G occur during G protein activation. J Biol Chem 274:2379–2385[Abstract/Free Full Text]
22. Muradov KG, Artemyev NO 2000 Coupling between the N- and C-terminal domains influences transducin- intrinsic GDP/GTP exchange. Biochemistry 39:3937–3942[CrossRef][Medline]
23. Bourne HR 1997 How receptors talk to trimeric G proteins. Curr Opin Cell Biol 9:134–142[CrossRef][Medline]
24. Bohm A, Gaudet R, Sigler PB 1997 Structural aspects of heterotrimeric G-protein signaling. Curr Opin Biotechnol 8:480–487[CrossRef][Medline]
25. Iiri T, Farfel Z, Bourne HR 1998 G-protein diseases furnish a model for the turn-on switch. Nature 394:35–38[CrossRef][Medline]
26. Ford CE, Skiba NP, Bae H, Daaka Y, Reuveny E, Shekter LR, Rosal R, Weng G, Yang C-S, Iyengar R, Miller RJ, Jan LY, Lefkowitz RJ, Hamm HE 1998 Molecular basis for interactions of G protein ß subunits with effectors. Science 280:1271–1274[Abstract/Free Full Text]
27. Schoneberg T, Schultz G, Gudermann T 1999 Structural basis of G protein-coupled receptor function. Mol Cell Endocrinol 151:181–193[CrossRef][Medline]
28. LeVine III H 1999 Structural features of heterotrimeric G-protein-coupled receptors and their modulatory proteins. Mol Neurobiol 19:111–149[Medline]
29. Wess J 1997 G-protein-coupled receptors: molecular mechanisms involved in receptor activation and selectivity of G-protein recognition. FASEB J 11:346–354[Abstract]
30. Conklin BR, Bourne HR 1993 Structural elements of G subunits that interact with Gß, receptors, and effectors. Cell 73:631–641[CrossRef][Medline]
31. Martin EL, Rens-Domiano S, Schatz PJ, Hamm HE 1996 Potent peptide analogues of a G protein receptor-binding region obtained with a combinatorial library. J Biol Chem 271:361–366[Abstract/Free Full Text]
32. Van Dop C, Yamanaka G, Steinberg F, Sekura RD, Manclark CR, Stryer L, Bourne H 1984 ADP-ribosylation of transducin by pertussis toxin blocks the light-stimulated hydrolysis of GTP and cGMP in retinal photoreceptors. J Biol Chem 259:23–26[Abstract/Free Full Text]
33. Unemori H, Inoue T, Kume S, Sekiyama N, Nagao M, Itoh H, Nakanishi S, Mikoshiba K, Yamamoto T 1997 Activation of G protein Gq/11 through tyrosine phosphorylation of the subunit. Science 276:1878–1881[Abstract/Free Full Text]
34. Barr A J, Brass LF, Manning DR 1997 Reconstitution of receptors and GTP-binding regulatory proteins (G proteins) in Sf9 cells. A direct evaluation of selectivity in receptor G protein coupling. J Biol Chem 272:2223–2229[Abstract/Free Full Text]
35. Berstein G, Blank JL, Smrcka AV, Higashijima T, Sternweis PC, Exton JH, Ross EM 1992 Reconstitution of agonist-stimulated phosphatidylinositol 4,5-bisphosphate hydrolysis using purified m1 muscarinic receptor, Gq/11, and phospholipase C-ß1. J Biol Chem 267:8081–8088[Abstract/Free Full Text]
36. Blahos 2nd J, Mary S, Perroy J, de Colle C, Brabet I, Bockaert J, Pin JP 1998 Extreme C terminus of G protein -subunits contains a site that discriminates between Gi-coupled metabotropic glutamate receptors. J Biol Chem 273:25765–25769[Abstract/Free Full Text]
37. Kostenis E, Gomeza J, Lerche C, Wess J 1997 Genetic analysis of receptor-Gq coupling selectivity. J Biol Chem 272:23675–23681[Abstract/Free Full Text]
38. Conklin BR, Herzmark P, Ishida S, Voyno-Yasenetskaya TA, Sun Y, Farfel Z, Bourne HR 1996 Carboxyl-terminal mutations of Gq and Gs that alter the fidelity of receptor activation. Mol Pharmacol 50:885–890[Abstract]
39. McFadzean I, Mullaney I, Brown DA, Milligan G 1989 Antibodies to the GTP binding protein, Go, antagonize noradrenaline-induced calcium current inhibition in NG108–15 hybrid cells. Neuron 3:177–182[CrossRef][Medline]
40. Hamm HE, Deretic D, Arendt A, Hargrave PA, Koenig B, Hofmann KP 1988 Site of G protein binding to rhodopsin mapped with synthetic peptides from the subunit. Science 241:832–835[Abstract/Free Full Text]
41. Dratz ED, Fursteneau JE, Lambert CG, Thireault DL, Rarick H, Schepers T, Pakhlevaniants S, Hamm HE 1993 NMR structure of a receptor-bound G-protein peptide. Nature 363:276–280[CrossRef][Medline]
42. Rasenick MM, Watanabe M, Lazarevic MB, Hatta S, Hamm HE 1994 Synthetic peptides as probes for G protein function. Carboxyl-terminal Gs peptides mimic Gs and evoke high affinity agonist binding to ß-adrenergic receptors. J Biol Chem 269:21519–21525[Abstract/Free Full Text]
43. Gilchrist A, Mazzoni MR, Dineen B, Dice A, Linden J, Proctor WR, Lupica CR, Dunwiddie TV, Hamm HE 1998 Antagonists of the receptor-G protein interface block Gi-coupled signal transduction. J Biol Chem 273:14912–14919[Abstract/Free Full Text]
44. Bae H, Anderson K, Flood LA, Skiba NP, Hamm HE, Graber SG 1997 Molecular determinants of selectivity in 5-hydroxytryptamine1B receptor-G protein interactions. J Biol Chem 272:32071–32077[Abstract/Free Full Text]
45. Bae H, Cabrera-Vera TM, Depree KM, Graber SG, Hamm HE 1999 Two amino acids within the 4 helix of G1 mediate coupling with 5-hydroxytryptamine1B receptors. J Biol Chem 274:14963–14971[Abstract/Free Full Text]
46. Taylor JM, Jacob-Mosier GG, Lawton RG, Remmers AE, Neubig RR 1994 Binding of an 2 adrenergic receptor third intracellular loop peptide to Gß and the amino terminus of G. J Biol Chem 269:27618–27624[Abstract/Free Full Text]
47. Onrust R, Herzmark P, Chi P, Garcia PD, Lichtarge O, Kingsley C, Bourne HR 1997 Receptor and ß binding sites in the subunit of the retinal G protein transducin. Science 275:381–384[Abstract/Free Full Text]
48. Lee CH, Katz A, Simon MI 1995 Multiple regions of G 16 contribute to the specificity of activation by the C5a receptor. Mol Pharmacol 47:218–223[Abstract]
49. Mazzoni MR, Hamm HE 1996 Interaction of transducin with light-activated rhodopsin protects it from proteolytic digestion by trypsin. J Biol Chem 271:30034–30040[Abstract/Free Full Text]
50. Kisselev O, Pronin A, Ermolaeva M, Gautam N 1995 Receptor-G protein coupling is established by a potential conformational switch in the ß complex. Proc Natl Acad Sci USA 92:9102–9106[Abstract/Free Full Text]
51. Kisselev O, Ermolaeva M, Gautam N 1995 Efficient interaction with a receptor requires a specific type of prenyl group on the G protein subunit. J Biol Chem 270:25356–25358[Abstract/Free Full Text]
52. Yasuda H, Lindorfer MA, Woodfork KA, Fletcher JE, Garrison JC 1996 Role of the prenyl group on the G protein subunit in coupling trimeric G proteins to A1 adenosine receptors. J Biol Chem 271:18588–18595[Abstract/Free Full Text]
53. McIntire WE, MacCleery G, Garrison JC 2001 The G protein ß subunit is a determinant in the coupling of G_s to the ß1-adrenergic and A_2a adenosine receptors. J Biol Chem 276:15801–15809[Abstract/Free Full Text]
54. Krieger-Brauer HI, Medda PK, Sattel B, Kather H 2000 Inhibitory effect of isoproterenol on NADPH-dependent H₂O₂ generation in human adipocyte plasma membranes is mediated by ß-subunits derived from Gs. J Biol Chem 275:2486–2490[Abstract/Free Full Text]
55. Cismowski MJ, Takesono A, Ma C, Lizano JS, Xie X, Fuernkranz H, Lanier SM, Duzic E 1999 Genetic screens in yeast to identify mammalian nonreceptor modulators of G-protein signaling. Nat Biotechnol 17:878–883[CrossRef][Medline]
56. Takesono A, Cismowski MJ, Ribas C, Bernard M, Chung P, Hazard 3rd S, Duzic E, Lanier SM 1999 Receptor-independent activators of heterotrimeric G-protein signaling pathways. J Biol Chem 274:33202–33205[Abstract/Free Full Text]
57. De Vries L, Fischer T, Tronchere H, Brothers GM, Strockbine B, Siderovski DP, Farquhar MG 2000 Activator of G protein signaling 3 is a guanine dissociation inhibitor for Gi subunits. Proc Natl Acad Sci USA 97:14364–14369[Abstract/Free Full Text]
58. Jamora C, Takizawa PA, Zaarour RF, Denesvre C, Faulkner DJ, Malhotra V 1997 Regulation of Golgi structure through heterotrimeric G proteins. Cell 91:617–626[CrossRef][Medline]
59. O’Dowd BF, Nguyen T, Tirpak A, Jarvie KR, Israel Y, Seeman P, Niznik HB 1990 Cloning of two additional catecholamine receptors from rat brain. FEBS Lett 262:8–12[CrossRef][Medline]
60. Van Tol HH 1998 Structural and functional characteristics of the dopamine D4 receptor. Adv Pharmacol 42:486–490
61. Gilchrist A, Bunemann M, Li A, Hosey MM, Hamm HE 1999 A dominant-negative strategy for studying roles of G proteins in vivo. J Biol Chem 274:6610–6616[Abstract/Free Full Text]
62. Gilchrist A, Vanhauwe JF, Li A, Thomas TO, Voyno-Yasenetskaya T, Hamm HE 2001 G minigenes expressing C-terminal peptides serve as specific inhibitors of thrombin-mediated endothelial activation. J Biol Chem 276:25672–25679[Abstract/Free Full Text]
63. Deleted in proof.
64. Walther W, Stein U 1996 Targeted vectors for gene therapy of cancer and retroviral infections. Mol Biotechnol 6:267–286[Medline]
65. Lutsiak CM, Sosnowski DL, Wishart DS, Kwon GS, Samuel J 1998 Use of a liposome antigen delivery system to alter immune responses in vivo. J Pharm Sci 87:1428–1432[CrossRef][Medline]
66. Chang M, Zhang L, Tam JP, Sanders-Bush E 2000 Dissecting G protein-coupled receptor signaling pathways with membrane-permeable blocking peptides. Endogenous 5-HT_2C receptors in choroid plexus epithelial cells. J Biol Chem 275:7021–7029[Abstract/Free Full Text]
67. Akhter SA, Luttrell LM, Rockman HA, Iaccarino G, Lefkowitz RJ, Koch WJ 1998 Targeting the receptor-Gq interface to inhibit in vivo pressure overload myocardial hypertrophy. Science 280:574–577[Abstract/Free Full Text]
68. Knall C, Johnson GL 1998 G-protein regulatory pathways: rocketing into the twenty-first century. J Cell Biochem 31:137–146
69. Taussig R, Zimmermann G 1998 Type-specific regulation of mammalian adenylyl cyclases by G protein pathways. Adv Sec Mess Phosphoprot Res 32:81–98[Medline]
70. Tesmer JJ, Sunahara RK, Gilman AG, Sprang SR 1997 Crystal structure of the catalytic domains of adenylyl cyclase in a complex with GsGTPS. Science 278:1907–1916[Abstract/Free Full Text]
71. Berlot CH, Bourne HR 1992 Identification of effector-activating residues of Gs. Cell 68:911–922[CrossRef][Medline]
72. Sunahara RK, Dessauer CW, Whisnant RE, Kleuss C, Gilman AG 1997 Interaction of Gs with the cytosolic domains of mammalian adenylyl cyclase. J Biol Chem 272:22265–22271[Abstract/Free Full Text]
73. Chidiac P, Ross EM 1999 Phospholipase C-ß1 directly accelerates GTP hydrolysis by Gq and acceleration is inhibited by Gß subunits. J Biol Chem 274:19639–19643[Abstract/Free Full Text]
74. Ghahremani MH, Cheng P, Lembo PM, Albert PR 1999 Distinct roles for Gi2, Gi3, and Gß in modulation of forskolin- or Gs-mediated cAMP accumulation and Ca²⁺ mobilization by dopamine D2S receptors. J Biol Chem 274:9238–9245[Abstract/Free Full Text]
75. Macrez-Lepretre N, Kalkbrenner F, Schultz G, Mironneau J 1997 Distinct functions of Gq and G11 proteins in coupling 1-adrenoreceptors to Ca ²⁺ release and Ca²⁺ entry in rat portal vein myocytes. J Biol Chem 272:5261–5268[Abstract/Free Full Text]
76. Jordan JD, Carey KD, Stork PJ, Iyengar R 1999 Modulation of rap activity by direct interaction of G_o with Rap1 GTPase-activating protein. J Biol Chem 274:21507–21510[Abstract/Free Full Text]
77. Chen LT, Gilman AG, Kozasa T 1999 A candidate target for G protein action in brain. J Biol Chem 274:26931–26938[Abstract/Free Full Text]
78. Lin P, Le-Niculescu H, Hofmeister R, McCaffery JM, Jin M, Hennemann H, McQuistan T, De Vries L, Farquhar MG 1998 The mammalian Ca²⁺-binding protein, nucleobindin (CALNUC), is a Golgi resident protein. J Cell Biol 141:1515–1527[Abstract/Free Full Text]
79. Mochizuki N, Hibi M, Kanai Y, Insel PA 1995 Interaction of the protein nucleobindin with Gi2, as revealed by the yeast two-hybrid system. FEBS Lett 373:155–158[CrossRef][Medline]
80. Lin P, Fischer T, Weiss T, Farquhar MG 2000 Calnuc, an EF-hand Ca²⁺ binding protein, specifically interacts with the C-terminal 5-helix of Gi3. Proc Natl Acad Sci USA 97:674–679[Abstract/Free Full Text]
81. Miura K, Kurosawa Y, Kanai Y 1994 Ca²⁺-binding activity of nucleobindin mediated by an EF hand moiety. Biochem Biophys Res Commun 199:1388–1393[CrossRef][Medline]
82. Bence K, Ma W, Kozasa T, Huang XY 1997 Direct stimulation of Bruton’s tyrosine kinase by G_q-protein -subunit. Nature 389:296–299[CrossRef][Medline]
83. Fields TA, Casey PJ 1997 Signalling functions and biochemical properties of pertussis toxin-resistant G-proteins. Biochem J 321:561–571
84. Hart MJ, Jiang X, Kozasa T, Roscoe W, Singer WD, Gilman AG, Sternweis PC, Bollag G 1998 Direct stimulation of the guanine nucleotide exchange activity of p115 RhoGEF by G13. Science 280:2112–2114[Abstract/Free Full Text]
85. Vaiskunaite R, Adarichev V, Furthmayr H, Kozasa T, Gudkov A, Voyno-Yasenetskaya TA 2000 Conformational activation of radixin by G13 protein subunit. J Biol Chem 275:26206–26212[Abstract/Free Full Text]
86. Vaiskunaite R, Kozasa T, Voyno-Yasenetskaya TA 2001 Interaction between the G subunit of heterotrimeric G12 protein and Hsp90 is required for G12 signaling. J Biol Chem 276:46088–46093[Abstract/Free Full Text]
87. Neer EJ 1995 Heterotrimeric G proteins: organizers of transmembrane signals. Cell 80:249–257[CrossRef][Medline]
88. Logothetis DE, Kurachi Y, Galper J, Neer EJ, Clapham DE 1987 The ß subunits of GTP-binding proteins activate the muscarinic K⁺ channel in heart. Nature 325:321–326[CrossRef][Medline]
89. Katz A, Wu D, Simon MI 1992 Subunits ß of heterotrimeric G protein activate ß2 isoform of phospholipase C. Nature 360:686–689[CrossRef][Medline]
90. Sternweis PC 1994 The active role of ß in signal transduction. Curr Opin Cell Biol 6:198–203[CrossRef][Medline]
91. Tang WJ, Gilman AG 1991 Type-specific regulation of adenylyl cyclase by G protein ß subunits. Science 254:1500–1503[Abstract/Free Full Text]
92. Pitcher JA, Inglese J, Higgins JB, Arriza JL, Casey PJ, Kim C, Benovic JL, Kwatra MM, Caron MG, Lefkowitz RJ 1992 Role of ß subunits of G proteins in targeting the ß-adrenergic receptor kinase to membrane-bound receptors. Science 257:1264–1267[Abstract/Free Full Text]
93. Stephens L, Smrcka A, Cooke FT, Jackson TR, Sternweis PC, Hawkins PT 1994 A novel phosphoinositide 3 kinase activity in myeloid-derived cells is activated by G protein ß subunits. Cell 77:83–93[CrossRef][Medline]
94. Tang X, Downes CP 1997 Purification and characterization of Gß-responsive phosphoinositide 3-kinases from pig platelet cytosol. J Biol Chem 272:14193–14199[Abstract/Free Full Text]
95. Inglese J, Koch WJ, Touhara K, Lefkowitz RJ 1995 Gß interactions with PH domains and Ras-MAPK signaling pathways. Trends Biol Sci 20:151–156
96. Reuveny E, Slesinger PA, Inglese J, Morales JM, Iniguez-Lluhi JA, Lefkowitz RJ, Bourne HR, Jan YN, Jan LY 1994 Activation of the cloned muscarinic potassium channel by G protein ß subunits. Nature 370:143–146[CrossRef][Medline]
97. Ikeda SR 1996 Voltage-dependent modulation of N-type calcium channels by G-protein ß subunits. Nature 380:255–258[CrossRef][Medline]
98. Herlitze S, Garcia DE, Mackie K, Hille B, Scheuer T, Catterall WA 1996 Modulation of Ca²⁺ channels by G-protein ß subunits. Nature 380:258–262[CrossRef][Medline]
99. Lupas AN, Lupas JM, Stock JB 1992 Do G-protein subunits associate via a three-stranded coiled coil? FEBS Lett 314:105–108[CrossRef][Medline]
100. Ray K, Kunsch C, Bonner LM, Robishaw JD 1995 Isolation of cDNA clones encoding eight different human G protein subunits, including three novel forms designated the 4, 10, and 11 subunits. J Biol Chem 270:21765–21771[Abstract/Free Full Text]
101. Simon MI, Strathmann MP, Gautam N 1991 Diversity of G proteins in signal transduction. Science 252:802–808[Abstract/Free Full Text]
102. Watson AJ, Aragay AM, Slepak VZ, Simon MI 1996 A novel form of the G protein ß subunit Gß5 is specifically expressed in the vertebrate retina. J Biol Chem 271:28154–28160[Abstract/Free Full Text]
103. Spring DJ, Neer EJ 1994 A 14-amino acid region of the G protein subunit is sufficient to conifer selectivity of binding to the ß subunit. J Biol Chem 269:22882–22886[Abstract/Free Full Text]
104. Schmidt CJ, Thomas TC, Levine MA, Neer EJ 1992 Specificity of G-protein ß and subunit interaction. J Biol Chem 267:13807–13810[Abstract/Free Full Text]
105. Garritsen A, Simonds WF 1994 Multiple domains of G protein ß confer subunit specificity in ß interaction. J Biol Chem 269:24418–24423[Abstract/Free Full Text]
106. Yan K, Kalyanaraman V, Gautam N 1996 Differential ability to form the G protein ß complex among members of the ß and subunit families. J Biol Chem 271:7141–7146[Abstract/Free Full Text]
107. Lindorfer MA, Myung CS, Savino Y, Yasuda H, Khazan R, Garrison JC 1998 Differential activity of the G protein ß52 subunit at receptors and effectors. J Biol Chem 273:34429–34436[Abstract/Free Full Text]
108. Lei Q, Jones MB, Talley EM, Schrier AD, McIntire WE, Garrison JC, Bayliss DA 2000 Activation and inhibition of G protein-coupled inwardly rectifying potassium (Kir3) channels by G protein ß subunits. Proc Natl Acad Sci USA 97:9771–9776[Abstract/Free Full Text]
109. Fawzi AB, Fay DS, Murphy EA, Tamir H, Erdos JJ, Northup JK 1991 Rhodopsin and the retinal G-protein distinguish among G-protein ß subunit forms. J Biol Chem 266:12194–12200[Abstract/Free Full Text]
110. Tamir H, Fawzi AB, Tamir A, Evans T, Northup JK 1991 G-protein ß forms: identity of ß and diversity of subunits. Biochemistry 30:3929–3936[CrossRef][Medline]
111. Iniguez-Lluhi JA, Simon MI, Robishaw JD, Gilman AG 1992 G protein ß subunits synthesized in Sf9 cells. J Biol Chem 267:23409–23417[Abstract/Free Full Text]
112. Ueda N, Iniguez-Lluhi JA, Lee E, Smrcka AV, Robishaw JD, Gilman AG 1994 G protein ß subunits. Simplified purification and properties of novel isoforms. J Biol Chem 269:4388–4395[Abstract/Free Full Text]
113. Bayewitch ML, Avidor-Reiss T, Levy R, Pfeuffer T, Nevo I, Simonds WF, Vogel Z 1998 Differential modulation of adenylyl cyclases I and II by various G ß subunits. J Biol Chem 273:2273–2276[Abstract/Free Full Text]
114. Zhang S, Coso OA, Lee C, Gutkind JS, Simonds WF 1996 Selective activation of effector pathways by brain-specific G protein ß5. J Biol Chem 271:33535–33539
115. Ruiz-Velasco V, Ikeda SR 2000 Multiple G-protein ß combinations produce voltage-dependent inhibition of N-type calcium channels in rat superior cervical ganglion neurons. J Neurosci 20:2183–2191[Abstract/Free Full Text]
116. Mirshahi T, Mittal V, Zhang H, Linder ME, Logothetis DE 2002 Distinct sites on G protein ß subunits regulate different effector functions. J Biol Chem 277:36345–36350[Abstract/Free Full Text]
117. Fletcher JE, Lindorfer MA, DeFilippo JM, Yasuda H, Guilmard M, Garrison JC 1998 The G protein ß5 subunit interacts selectively with the Gq subunit. J Biol Chem 273:636–644[Abstract/Free Full Text]
118. Figler RA, Graber SG, Lindorfer MA, Yasuda H, Linden J, Garrison JC 1996 Reconstitution of recombinant bovine A1 adenosine receptors in Sf9 cell membranes with recombinant G proteins of defined composition. Mol Pharmacol 50:1587–1595[Abstract]
119. Gaudet R, Bohm A, Sigler PB 1996 Crystal structure at 2.4 Å resolution of the complex of transducin ß and its regulator, phosducin. Cell 87:577–588[CrossRef][Medline]
120. Panchenko MP, Saxena K, Li Y, Charnecki S, Sternweis PM, Smith TF, Gilman AG, Kozasa T, Neer EJ 1998 Sites important for PLCß2 activation by the G protein ß subunit map to the sides of the ß propeller structure. J Biol Chem 273:28298–28304[Abstract/Free Full Text]
121. Li Y, Sternweis PM, Charnecki S, Smith TF, Gilman AG, Neer EJ, Kozasa T 1998 Sites for G binding on the G protein ß subunit overlap with sites for regulation of phospholipase Cß and adenylyl cyclase. J Biol Chem 273:16265–16272[Abstract/Free Full Text]
122. Burack WR, Shaw AS 2000 Signal transduction: hanging on a scaffold. Curr Opin Cell Biol 12:211–216[CrossRef][Medline]
123. Jamora C, Yamanouye N, Van Lint J, Laudenslager J, Vandenheede JR, Faulkner DJ, Malhotra V 1999 Gß-mediated regulation of Golgi organization is through the direct activation of protein kinase D. Cell 98:59–68[CrossRef][Medline]
124. Roychowdhury S, Rasenick MM 1997 G protein ß12 subunits promote microtubule assembly. J Biol Chem 272:31576–31581[Abstract/Free Full Text]
125. Bell B, Xing H, Yan K, Gautam N, Muslin AJ 1999 KSR-1 binds to G-protein ß subunits and inhibits ß-induced mitogen-activated protein kinase activation. J Biol Chem 274:7982–7986[Abstract/Free Full Text]
126. Lin HC, Gilman AG 1996 Regulation of dynamin I GTPase activity by G protein ß subunits and phosphatidylinositol 4,5-bisphosphate. J Biol Chem 271:27979–27982[Abstract/Free Full Text]
127. Pumiglia KM, LeVine H, Haske T, Habib T, Jove R, Decker SJ 1995 A direct interaction between G-protein ß subunits and the Raf-1 protein kinase. J Biol Chem 270:4251–4254
128. Langhans-Rajasekaran SA, Wan Y, Huang XY 1995 Activation of Tsk and Btk tyrosine kinases by G protein ß subunits. Proc Natl Acad Sci USA 92:8601–8605[Abstract/Free Full Text]
129. Liu M, Yu B, Nakanishi O, Wieland T, Simon M 1997 The Ca²⁺-dependent binding of calmodulin to an N-terminal motif of the heterotrimeric G protein ß subunit. J Biol Chem 272:18801–18807[Abstract/Free Full Text]
130. Pellegrino S, Zhang S, Garritsen A, Simonds WF 1997 The coiled-coil region of the G protein ß subunit. Mutational analysis of G and effector interactions. J Biol Chem 272:25360–25366[Abstract/Free Full Text]
131. Dell EJ, Connor J, Chen S, Stebbins EG, Skiba NP, Mochly-Rosen D, Hamm HE 2002 The ß subunit of heterotrimeric G proteins interacts with RACK1 and two other WD repeat proteins. J Biol Chem 277:49888–49895[Abstract/Free Full Text]
132. Blackmer T, Larsen EC, Takahashi M, Martin TF, Alford S, Hamm HE 2001 G protein ß subunit-mediated presynaptic inhibition: regulation of exocytotic fusion downstream of Ca²⁺ entry. Science 292:293–297[Abstract/Free Full Text]
133. Gautam N, Downes GB, Yan K, Kisselev O 1998 The G-protein ß complex. Cell Signal 10:447–455[CrossRef][Medline]
134. Watson AJ, Katz A, Simon MI 1994 A fifth member of the mammalian G-protein ß-subunit family. Expression in brain and activation of the ß2 isotype of phospholipase C. J Biol Chem 269:22150–22156[Abstract/Free Full Text]
135. Garritsen A, van Galen PJ, Simonds WF 1993 The N-terminal coiled-coil doman of ß is essential for association: a model for G-protein ß subunit interaction. Proc Natl Acad Sci USA 90:7706–7710[Abstract/Free Full Text]
136. Cabrera JL, de Freitas F, Satpaev DK, Slepak VZ 1998 Identification of the Gß5-RGS7 protein complex in the retina. Biochem Biophys Res Commun 249:898–902[CrossRef][Medline]
137. Yoshikawa DM, Hatwar M, Smrcka AV 2000 G protein ß5 subunit interactions with subunits and effectors. Biochemistry 39:11340–11347[CrossRef][Medline]
138. Makino ER, Handy JW, Li T, Arshavsky VY 1999 The GTPase activating factor for transducin in rod photoreceptors is the complex between RGS9 and type 5 G protein ß subunit. Proc Natl Acad Sci USA 96:1947–1952[Abstract/Free Full Text]
139. Levay K, Cabrera JL, Satpaev DK, Slepak VZ 1999 Gß5 prevents the RGS7-Go interaction through binding to a distinct G-like domain found in RGS7 and other RGS proteins. Proc Natl Acad Sci USA 96:2503–2507[Abstract/Free Full Text]
140. Snow BE, Krumins AM, Brothers GM, Lee SF, Wall MA, Chung S, Mangion J, Arya S, Gilman AG, Siderovski DP 1998 A G protein subunit-like domain shared between RGS11 and other RGS proteins specifies binding to Gß5 subunits. Proc Natl Acad Sci USA 95:13307–13312[Abstract/Free Full Text]
141. Kovoor A, Chen CK, He W, Wensel TG, Simon MI, Lester HA 2000 Co-expression of Gß5 enhances the function of two G subunit-like domain-containing regulators of G protein signaling proteins. J Biol Chem 275:3397–3402[Abstract/Free Full Text]
142. Posner BA, Gilman AG, Harris BA 1999 Regulators of G protein signalling 6 and 7. J Biol Chem 274:31087–31093[Abstract/Free Full Text]
143. Chen CK, Burns ME, He W, Wensel TG, Baylor DA, Simon MI 2000 Slowed recovery of rod photoresponse in mice lacking the GTPase accelerating protein RGS9–1. Nature 403:557–560[CrossRef][Medline]
144. Graziano MP, Freissmuth M, Gilman AG 1989 Expression of Gs in Escherichia coli. Purification and properties of two forms of the protein. J Biol Chem 264:409–418[Abstract/Free Full Text]
145. Higashijima T, Ferguson KM, Smigel MD, Gilman AG 1987 The effect of GTP and Mg²⁺ on the GTPase activity and the fluorescent properties of Go. J Biol Chem 262:757–761[Abstract/Free Full Text]
146. Warner DR, Weinstein LS 1999 A mutation in the heterotrimeric stimulatory guanine nucleotide binding protein -subunit with impaired receptor-mediated activation because of elevated GTPase activity. Proc Natl Acad Sci USA 96:4268–4272[Abstract/Free Full Text]
147. Arshavsky VY, Pugh EN 1998 Lifetime regulation of G protein effector complex: emerging importance of RGS proteins. Neuron 20:11–14[CrossRef][Medline]
148. Zerangue N, Jan LY 1998 G-protein signaling: fine-tuning signaling kinetics. Curr Biol 8:R313–R316
149. Bernstein G, Blank JL, Jhon DY, Exton JH, Rhee SG, Ross EM 1992 Phospholipase C-ß1 is a GTPase-activating protein for Gq/11, its physiologic regulator. Cell 70:411–418[CrossRef][Medline]
150. Biddlecome GH, Berstein G, Ross EM 1996 Regulation of phospholipase C-ß1 by Gq and m1 muscarinic cholinergic receptor. Steady-state balance of receptor-mediated activation and GTPase-activating protein-promoted deactivation. J Biol Chem 271:7999–8007[Abstract/Free Full Text]
151. Arshavsky VY, Bownds MD 1992 Regulation of deactivation of photoreceptor G protein by its target enzyme and cGMP. Nature 357:416–417[CrossRef][Medline]
152. Scholich K, Mullenix JB, Wittpoth C, Poppleton HM, Pierre SC, Lindorfer MA, Garrison JC, Patel TB 1999 Facilitation of signal onset and termination by adenylyl cyclase. Science 283:1328–1331[Abstract/Free Full Text]
153. Bunemann M, Hosey MM 1998 Regulators of G protein signaling (RGS) proteins constitutively activate Gß-gated potassium channels. J Biol Chem 273:31186–31190[Abstract/Free Full Text]
154. De Vries L, Zheng B, Fischer T, Elenko E, Farquhar MG 2000 The regulator of G protein signaling family. Annu Rev Pharmacol Toxicol 40:235–271[CrossRef][Medline]
155. Ross EM, Wilkie TM 2000 GTPase-activating proteins for heterotrimeric G proteins: regulators of G protein signaling (RGS) and RGS-like proteins. Annu Rev Biochem 69:795–827[CrossRef][Medline]
156. Hollinger S, Hepler JR 2002 Cellular regulation of RGS proteins: modulators and integrators of G protein signaling. Pharmacol Rev 54:527–559[Abstract/Free Full Text]
157. Dohlman HG, Song J, Ma D, Courchesne WE, Thorner J 1996 Sst2, a negative regulator of pheromone signaling in the yeast Saccharomyces cerevisiae: expression, localization, and genetic interaction and physical association with Gp1 (the G-protein subunit). Mol Cell Biol 16:5194–5209[Abstract]
158. Koelle MR, Horvitz HR 1996 EGL-10 regulates G protein signaling in the C. elegans nervous system and shares a conserved domain with many mammalian proteins. Cell 84:115–125[CrossRef][Medline]
159. De Vries L, Mousli M, Wurmser A, Farquhar MG 1995 GAIP, a protein that specifically interacts with the trimeric G protein Gi3, is a member of a protein family with a highly conserved core domain. Proc Natl Acad Sci USA 92:11916–11920[Abstract/Free Full Text]
160. Chen C, Zheng B, Han J, Lin S-C 1997 Characterization of a novel mammalian RGS protein that binds to G proteins and inhibits pheromone signaling in yeast. J Biol Chem 272:8679–8685[Abstract/Free Full Text]
161. Dohlman HG, Thorner J 1997 RGS proteins and signaling by heterotrimeric G proteins. J Biol Chem 272:3871–3874[Free Full Text]
162. He W, Cowan CW, Wensel TG 1998 RGS9, a GTPase accelerator for phototransduction. Neuron 20:95–102[CrossRef][Medline]
163. Skiba NP, Yang C-S, Huang T, Bae H, Hamm HE 1999 The helical domain of Gt determines specific interaction with RGS9. J Biol Chem 274:8770–8778[Abstract/Free Full Text]
164. Chen C, Lin SC 1998 The core domain of RGS16 retains G-protein binding and GAP activity in vitro, but is not functional in vivo. FEBS Lett 422:359–362[CrossRef][Medline]
165. He W, Lu L, Zhang X, El-Hodiri HM, Chen CK, Slep KC, Simon MI, Jamrich M, Wensel TG 2000 Modules in the photoreceptor RGS9–1.Gß 5L GTPase-accelerating protein complex control effector coupling, GTPase acceleration, protein folding, and stability. J Biol Chem 275:37093–37100[Abstract/Free Full Text]
166. Siderovski DP, Strockbine B, Behe CI 1999 Whither goest the RGS proteins? Crit Rev Biochem Mol Biol 34:215–251[CrossRef][Medline]
167. Tesmer JJ, Berman DM, Gilman AG, Sprang SR 1997 Structure of RGS4 bound to AlF₄^--activated Gi1: stabilization of the transition state for GTP hydrolysis. Cell 89:251–261[CrossRef][Medline]
168. Mukhopadhyay S, Ross EM 1999 Rapid GTP binding and hydrolysis by Gq promoted by receptor and GTPase-activating proteins. Proc Natl Acad Sci USA 96:9539–9544[Abstract/Free Full Text]
169. Yong-Chao Ma, Jianyun Huang, Shariq Ali, William Lowry, Xin-Yun Huang 2000 Src tyrosine kinase is a novel direct effector of G proteins. Cell 102:635–646[CrossRef][Medline]
170. Skiba NP, Hopp JA, Arshavsky VY 2000 The effector enzyme regulates the duration of G protein signaling in vertebrate photoreceptors by increasing the affinity between transducin and RGS protein. J Biol Chem 275:32716–32720[Abstract/Free Full Text]
171. Bushfield M, Murphy GJ, Lavan BE, Parker PJ, Hruby VJ, Milligan G, Houslay MD 1990 Hormonal regulation of Gi2-subunit phosphorylation in intact hepatocytes. Biochem J 268:449–457[Medline]
172. Strassheim D, Malbon CC 1994 Phosphorylation of Gi2 attenuates inhibitory adenylyl cyclase in neuroblastoma/glioma hybrid (NG-108–15) cells. J Biol Chem 269:14307–14313[Abstract/Free Full Text]
173. Murthy KS, Grider JR, Makhlouf GM 2000 Heterologous desensitization of response mediated by selective PKC-dependent phosphorylation of Gi-1 and Gi-2. Am J Physiol Cell Physiol 279:C925–C934
174. Chen CA, Manning DR 2001 Regulation of G proteins by covalent modification. Oncogene 20:1643–1652[CrossRef][Medline]
175. Fields TA, Casey PJ 1995 Phosphorylation of Gz by protein kinase C blocks interaction with the ß complex. J Biol Chem 270:23119–23125[Abstract/Free Full Text]
176. Carlson KE, Brass LF, Manning DR 1989 Thrombin and phorbol esters cause the selective phosphorylation of a G protein other than Gi in human platelets. J Biol Chem 264:13298–13305[Abstract/Free Full Text]
177. Glick JL, Meigs TE, Miron A, Casey PJ 1998 RGSZ1, a Gz-selective regulator of G protein signaling whose action is sensitive to the phosphorylation state of Gz. J Biol Chem 273:26008–26013[Abstract/Free Full Text]
178. Moyers JS, Linder ME, Shannon JD, Parsons SJ 1995 Identification of the in vitro phosphorylation sites on Gs mediated by pp60c-src. Biochemistry 305:411–417
179. Zick Y, Sagi-Eisenberg R, Pines M, Gierschik P, Spiegel AM 1986 Multisite phosphorylation of the subunit of transducin by the insulin receptor kinase and protein kinase C. Proc Natl Acad Sci USA 83:9294–9297[Abstract/Free Full Text]
180. Kozasa T, Gilman AG 1996 Protein kinase C phosphorylates G12 and inhibits its interaction with Gß. J Biol Chem 271:12562–12567[Abstract/Free Full Text]
181. Wieland T, Nurnberg B, Ulibarri I, Kaldenberg-Stasch S, Schultz G, Jakobs KH 1993 Guanine nucleotide-specific phosphate transfer by guanine nucleotide-binding regulatory protein ß-subunits. Characterization of the phosphorylated amino acid. J Biol Chem 268:18111–18118[Abstract/Free Full Text]
182. Asano T, Morishita R, Ueda H, Asano M, Kato K 1998 GTP-binding protein 12 subunit phosphorylation by protein kinase C. Identification of the phosphorylation site and factors involved in cultured cells and rat tissues in vivo. Eur J Biochem 251:314–319[Medline]
183. Yasuda H, Lindorfer MA, Myung C-S, Garrison JC 1998 Phosphorylation of the G protein 12 subunit regulates effector specificity. J Biol Chem 273:21958–21965[Abstract/Free Full Text]
184. Mumby SM, Heukeroth RO, Gordon JI, Gilman AG 1990 G-protein -subunit expression, myristoylation, and membrane association in COS cells. Proc Natl Acad Sci USA 87:728–732[Abstract/Free Full Text]
185. Milligan G, Grassie MA 1997 How do G proteins stay at the plasma membrane. Essays Biochem 32:49–60[Medline]
186. Wedegaertner PB 1998 Lipid modifications and membrane targeting of G. Biol Signals Recept 7:125–135[CrossRef][Medline]
187. Resh MD 1999 Fatty acylation of proteins: new insights into membrane targeting of myristoylated and palmitoylated proteins. Biochim Biophys Acta 1451:1–16[Medline]
188. Mumby SM 1997 Reversible palmitoylation of signaling proteins. Curr Opin Cell Biol 9:148–154[CrossRef][Medline]
189. Dunphy JT, Linder ME 1998 Signaling function of protein palmitoylation. Biochim Biophys Acta 1436:245–261[Medline]
190. Milligan G, Parenti M, Magee AI 1995 The dynamic role of palmitoylation in signal transduction. Trends Biochem Sci 20:181–186[CrossRef][Medline]
191. Zang FL, Casey PJ 1996 Protein prenylation: molecular mechanisms and functional consequences. Annu Rev Biochem 65:241–269[CrossRef][Medline]
192. Casey PJ 1995 Mechanisms of protein prenylation and role in G protein function. Biochem Soc Trans 23:161–166[Medline]
193. Fukada Y, Matsuda T, Kokame K, Takao T, Shimonishi Y, Akino T, Yoshizawa T 1994 Effects of carboxyl methylation of photoreceptor G protein -subunit in visual transduction. J Biol Chem 269:5163–5170[Abstract/Free Full Text]
194. Degtyarev MY, Spiegel AM, Jones TLZ 1994 Palmitoylation of a G protein i subunit requires membrane localization not myristoylation. J Biol Chem 269:30898–30903[Abstract/Free Full Text]
195. Morales J, Fishburn CS, Wilson PT, Bourne HR 1998 Plasma membrane localization of Gz requires two signals. Mol Biol Cell 10:1–14
196. Mumby SM, Kleuss C, Gilman AG 1994 Receptor regulation of G-protein palmitoylation. Proc Natl Acad Sci USA 91:2800–2804[Abstract/Free Full Text]
197. Wise A, Grassie MA, Parenti M, Lee M, Rees S, Milligan G 1997 A cysteine-3 to serine mutation of the G-protein Gi1 abrogates functional activation by the 2A-adrenoceptor but not interactions with the ß complex. Biochemistry 36:10620–10629[CrossRef][Medline]
198. Hallak H, Brass L, Manning D 1994 Failure to myristoylate the subunit of Gz is correlated with an inhibition of palmitoylation and membrane attachment, but has no affect on phosphorylation by protein kinase C. J Biol Chem 269:4571–4576[Abstract/Free Full Text]
199. Wilson PT, Bourne HR 1995 Fatty acylation of z. Eeffects of palmitoylation and myristoylation on z signaling. J Biol Chem 270:9667–9675[Abstract/Free Full Text]
200. Shahinian S, Silvius JR 1995 Doubly-lipid-modified protein sequence motifs exhibit long-lived anchorage to lipid bilayer membranes. Biochemistry 34:3813–3822[CrossRef][Medline]
201. McCabe JB, Berthiaume LG 1999 Functional roles for fatty acylated amino-terminal domains in subcellular localization. Mol Biol Cell 10:3771–3786[Abstract/Free Full Text]
202. Wang Y, Windh RT, Chen CA, Manning DR 1999 N-Myristoylation and ß play roles beyond anchorage in the palmitoylation of the G protein o subunit. J Biol Chem 274:37435–37442[Abstract/Free Full Text]
203. Wedegaertner P, Chu D, Wilson P, Levis M, Bourne H 1993 Palmitoylation is required for signaling functions and membrane attachment of Gq and Gs. J Biol Chem 268:25001–25008[Abstract/Free Full Text]
204. Degtyarev MY, Spiegel AM, Jones TLZ 1993 The G protein s subunit incorporates [³H]palmitic acid and mutation of cysteine-3 prevents this modification. Biochemistry 32:8057–8061[CrossRef][Medline]
205. Wise A, Parenti M, Milligan G 1997 Interaction of the G-protein G11 with receptors and phosphoinositidase C: the contribution of G-protein palmitoylation and membrane association. FEBS Lett 407:257–260[CrossRef][Medline]
206. Bhattacharyya R, Wedegaetner PB 2000 G13 requires palmitoylation for plasma membrane localization, Rho-dependent signaling, and promotion of p115-RhoGEF membrane binding. J Biol Chem 275:14992–14999[Abstract/Free Full Text]
207. Evanko DS, Thiygarajan MM, Wedegaertner PB 2000 Interaction with Gß is required for membrane targeting and palmitoylation of Gs and Gq. J Biol Chem 275:1327–1336[Abstract/Free Full Text]
208. Hepler J, Biddlecome G, Kleuss C, Camp L, Hofmann S, Ross E, Gilman A 1996 Functional importance of the amino terminus of Gq. J Biol Chem 271:496–504[Abstract/Free Full Text]
209. Fishburn CS, Pollitt SK, Bourne HR 2000 Localization of a peripheral membrane protein: Gß targets Gz. Proc Natl Acad Sci USA 97:1085–1090[Abstract/Free Full Text]
210. Linder ME, Pang IH, Duronio RJ, Gordon JI, Sternweis PC, Gilman AG 1991 Lipid modifications of G protein subunits. Myristoylation of Go increases its affinity for ß. J Biol Chem 266:4654–4659[Abstract/Free Full Text]
211. Taussig R, Iniguez-Lluhi JA, Gilman AG 1993 Inhibition of adenylyl cyclase by Gi. Science 261:218–221[Abstract/Free Full Text]
212. Iiri T, Backlund Jr PS, Jones TL, Wedegaertner PB, Bourne HR 1996 Reciprocal regulation of Gs by palmitate and the ß subunit. Proc Natl Acad Sci USA 93:14592–14597[Abstract/Free Full Text]
213. Tu Y, Wang J, Ross EM 1997 Inhibition of brain GzGAP and other RGS proteins by palmitoylation of G protein subunits. Science 278:1132–1135[Abstract/Free Full Text]
214. Degtyarev MY, Spiegel AM, Jones TLZ 1993 Increased palmitoylation of the Gs protein subunit after activation by the ß-adrenergic receptor or cholera toxin. J Biol Chem 268:23769–23772[Abstract/Free Full Text]
215. Wedegaertner PB, Wilson PT, Bourne HR 1995 Lipid modifications of trimeric G proteins. J Biol Chem 270:503–506[Free Full Text]
216. Matsuda T, Hashimoto Y, Ueda H, Asano T, Matsuura Y, Doi T, Takao T, Shimonishi Y, Fukada Y 1998 Specific isoprenyl group linked to transducin -subunit is a determinant of its unique signaling properties among G-proteins. Biochemistry 37:9843–9850[CrossRef][Medline]
217. Schwindinger WF, Robishaw JD 2001 Heterotrimeric G-protein ß-dimers in growth and differentiation. Oncogene 20:1653–1660[CrossRef][Medline]
218. Myung CS, Yasuda H, Liu WW, Harden TK, Garrison JC 1999 Role of isoprenoid lipids on the heterotrimeric G protein subunit in determining effector activation. J Biol Chem 274:16595–16603[Abstract/Free Full Text]
219. Parish CA, Smrcka AV, Rando RR 1995 Functional significance of ß subunit carboxymethylation for the activation of phospholipase C and phosphoinositide 3-kinase. Biochemistry 34:7722–7727[CrossRef][Medline]
220. Leopoldt D, Hanck T, Exner T, Maier U, Wetzker R, Nurnberg B 1998 Gß stimulates phosphoinositide 3-kinase- by direct interaction with two domains of the catalytic p110 subunit. J Biol Chem 273:7024–7029[Abstract/Free Full Text]
221. Erickson JW, Cerione RA 1991 Resonance energy transfer as a direct monitor of GTP-binding protein-effector interactions: activated -transducin binding to the cGMP phosphodiesterase in the bovine phototransduction cascade. Biochemistry 30:7112–7118[CrossRef][Medline]
222. Remmers AE 1998 Detection and quantitation of heterotrimeric G proteins by fluorescence resonance energy transfer. Anal Biochem 257:89–94[CrossRef][Medline]
223. Lan KL, Remmers AE, Neubig RR 1998 Roles of Go tryptophans in GTP hydrolysis, GDP release, and fluorescence signals. Biochemistry 37:837–843[CrossRef][Medline]
224. Farrens DL, Altenbach C, Yang K, Hubbell WL, Khorana HG 1996 Requirement of rigid-body motion of transmembrane helices for light activation of rhodopsin. Science 274:768–770[Abstract/Free Full Text]
225. Medkova M, Preininger AM, Yu NJ, Hubbell WL, Hamm HE 2002 Conformational changes in the amino-terminal helix of the G protein i1 following dissociation from Gß subunit and activation. Biochemistry 41:9962–9972[CrossRef][Medline]
226. Figler RA, Lindorfer MA, Graber SG, Garrison JC, Linden J 1997 Reconstitution of bovine A1 adenosine receptors and G proteins in phospholipid vesicles: ß-subunit composition influences guanine nucleotide exchange and agonist binding. Biochemistry 36:16288–16299[CrossRef][Medline]
227. Cooper MA, Hansson A, Lofas S, Williams DH 2000 A vesicle capture sensor chip for kinetic analysis of interactions with membrane-bound receptors. Anal Biochem 277:196–205[CrossRef][Medline]
228. Ram PT, Iyengar R 2001 G protein coupled receptor signaling through the Src and Stat3 pathway: role in proliferation and transformation. Oncogene 20:1601–1606[CrossRef][Medline]
229. Kinoshita M, Nukada T, Asano T, Mori Y, Akaike A, Satoh M, Kaneko S 2001 Binding of Go N terminus is responsible for the voltage-resistant inhibition of 1A (P/Q-type, Ca_v2.1) Ca²⁺ channels. J Biol Chem 276:28731–28738[Abstract/Free Full Text]
230. Peleg S, Varon D, Ivanina T, Dessauer CW, Dascal N 2002 Gi controls the gating of the G protein-activated K⁺ channel, GIRK. Neuron 33:87–99[CrossRef][Medline]
231. Roychowdhury S, Panda D, Wilson L, Rasenick MM 1999 G protein subunits activate tubulin GTPase and modulate microtubule polymerization dynamics. J Biol Chem 274:13485–13490[Abstract/Free Full Text]
232. Dhanasekaran N, Prasad MV, Wadsworth SJ, Dermott JM, van Rossum G 1994 Protein kinase C-dependent and -independent activation of Na⁺/H⁺ exchanger by G12 class of G proteins. J Biol Chem 269:11802–11806[Abstract/Free Full Text]
233. Plonk SG, Park SK, Exton JH 1998 The -subunit of the heterotrimeric G protein G13 activates a phospholipase D isozyme by a pathway requiring Rho family GTPases. J Biol Chem 273:4823–4826[Abstract/Free Full Text]
234. Kitamura K, Singer WD, Star RA, Muallem S, Miller RT 1996 Induction of inducible nitric-oxide synthase by the heterotrimeric G protein G13. J Biol Chem 271:7412–7415[Abstract/Free Full Text]
235. Touhara K, Hawes BE, van Biesen T, Lefkowitz RJ 1995 G protein ß subunits stimulate phosphorylation of Shc adapter protein. Proc Natl Acad Sci USA 92:9284–9287[Abstract/Free Full Text]
236. Mattingly RR, Macara IG 1996 Phosphorylation-dependent activation of the Ras-GRF/CDC25Mm exchange factor by muscarinic receptors and G-protein ß subunits. Nature 382:268–272[CrossRef][Medline]
237. Sunahara RK, Tesmer JJ, Gilman AG, Sprang SR 1997 Crystal structure of the adenylyl cyclase activator Gs. Science 278:1943–1947[Abstract/Free Full Text]
238. Mixon MB, Lee E, Coleman DE, Berghuis AM, Gilman AG, Sprang SR 1995 Tertiary and quaternary structural changes in Gi1 induced by GTP hydrolysis. Science 270:954–960[Abstract/Free Full Text]
239. Sondek J, Bohm A, Lambright DG, Hamm HE, Sigler PB 1996 Crystal structure of a G protein ß dimer at 2.1 Å resolution. Nature 379:369–374[CrossRef][Medline]
240. Palczewski K, Kumasaka T, Hori T, Behnke CA, Motoshima H, Fox BA, Le Trong I, Teller DC, Okada T, Stenkamp RE, Yamamoto M, Miyano M 2000 Crystal structure of rhodopsin: A G protein-coupled receptor. Science 289:739–745[Abstract/Free Full Text]
241. Neves SR, Ram PT, Iyengar R 2002 G protein pathways. Science 296:1636–1639[Abstract/Free Full Text]

This article has been cited by other articles:

				A. B. Perez-Oliva, C. Olivares, C. Jimenez-Cervantes, and J. C. Garcia-Borron Mahogunin Ring Finger-1 (MGRN1) E3 Ubiquitin Ligase Inhibits Signaling from Melanocortin Receptor by Competition with G{alpha}s J. Biol. Chem., November 13, 2009; 284(46): 31714 - 31725. [Abstract] [Full Text] [PDF]

				H.-J. Hippe, N. M. Wolf, I. Abu-Taha, R. Mehringer, S. Just, S. Lutz, F. Niroomand, E. H. Postel, H. A. Katus, W. Rottbauer, et al. The interaction of nucleoside diphosphate kinase B with G{beta}{gamma} dimers controls heterotrimeric G protein function PNAS, September 22, 2009; 106(38): 16269 - 16274. [Abstract] [Full Text] [PDF]

				A. E. Lyashkov, T. M. Vinogradova, I. Zahanich, Y. Li, A. Younes, H. B. Nuss, H. A. Spurgeon, V. A. Maltsev, and E. G. Lakatta Cholinergic receptor signaling modulates spontaneous firing of sinoatrial nodal cells via integrated effects on PKA-dependent Ca2+ cycling and IKACh Am J Physiol Heart Circ Physiol, September 1, 2009; 297(3): H949 - H959. [Abstract] [Full Text] [PDF]

				C. Le Goff, C. E. Lamien, E. Fakhfakh, A. Chadeyras, E. Aba-Adulugba, G. Libeau, E. Tuppurainen, D. B. Wallace, T. Adam, R. Silber, et al. Capripoxvirus G-protein-coupled chemokine receptor: a host-range gene suitable for virus animal origin discrimination J. Gen. Virol., August 1, 2009; 90(8): 1967 - 1977. [Abstract] [Full Text] [PDF]

				H.-H. Chen, W.-J. Lee, C. S. Fann, C. Bouchard, and W.-H. Pan Severe obesity is associated with novel single nucleotide polymorphisms of the ESR1 and PPAR{gamma} locus in Han Chinese Am. J. Clinical Nutrition, August 1, 2009; 90(2): 255 - 262. [Abstract] [Full Text] [PDF]

				J. Wang, P. Sengupta, Y. Guo, U. Golebiewska, and S. Scarlata Evidence for a Second, High Affinity G{beta}{gamma} Binding Site on G{alpha}i1(GDP) Subunits J. Biol. Chem., June 19, 2009; 284(25): 16906 - 16913. [Abstract] [Full Text] [PDF]

				A. C. Howlett, A. J. Gray, J. M. Hunter, and B. M. Willardson Role of Molecular Chaperones in G Protein {beta}5/Regulator of G Protein Signaling Dimer Assembly and G Protein {beta}{gamma} Dimer Specificity J. Biol. Chem., June 12, 2009; 284(24): 16386 - 16399. [Abstract] [Full Text] [PDF]

				Y. Hakak, K. Lehmann-Bruinsma, S. Phillips, T. Le, C. Liaw, D. T. Connolly, and D. P. Behan The role of the GPR91 ligand succinate in hematopoiesis J. Leukoc. Biol., May 1, 2009; 85(5): 837 - 843. [Abstract] [Full Text] [PDF]

				H. Zhu, G.-J. Li, L. Ding, X. Cui, H. Berg, S. M. Assmann, and Y. Xia Arabidopsis Extra Large G-Protein 2 (XLG2) Interacts with the G{beta} Subunit of Heterotrimeric G Protein and Functions in Disease Resistance Mol Plant, May 1, 2009; 2(3): 513 - 525. [Abstract] [Full Text] [PDF]

				Y. Zhang, R. D. Nelson, N. G. Carlson, C. D. Kamerath, D. E. Kohan, and B. K. Kishore Potential role of purinergic signaling in lithium-induced nephrogenic diabetes insipidus Am J Physiol Renal Physiol, May 1, 2009; 296(5): F1194 - F1201. [Abstract] [Full Text] [PDF]

				R. Dominguez, E. Hu, M. Zhou, and M. Baudry 17{beta}-Estradiol-Mediated Neuroprotection and ERK Activation Require a Pertussis Toxin-Sensitive Mechanism Involving GRK2 and {beta}-Arrestin-1 J. Neurosci., April 1, 2009; 29(13): 4228 - 4238. [Abstract] [Full Text] [PDF]

				K. RIEMANN, H. STRUWE, H. ALAKUS, B. OBERMAIER, K. J. SCHMITZ, K. W. SCHMID, and W. SIFFERT Association of GNB4 Intron-1 Haplotypes with Survival in Patients with UICC Stage III and IV Colorectal Carcinoma Anticancer Res, April 1, 2009; 29(4): 1271 - 1274. [Abstract] [Full Text] [PDF]

				K. Yamada, T. Hirotsu, M. Matsuki, H. Kunitomo, and Y. Iino GPC-1, a G Protein {gamma}-Subunit, Regulates Olfactory Adaptation in Caenorhabditis elegans Genetics, April 1, 2009; 181(4): 1347 - 1357. [Abstract] [Full Text] [PDF]

				M. Scarselli and J. G. Donaldson Constitutive Internalization of G Protein-coupled Receptors and G Proteins via Clathrin-independent Endocytosis J. Biol. Chem., February 6, 2009; 284(6): 3577 - 3585. [Abstract] [Full Text] [PDF]

				Y. Oka, L. R. Saraiva, Y. Y. Kwan, and S. I. Korsching The fifth class of G{alpha} proteins PNAS, February 3, 2009; 106(5): 1484 - 1489. [Abstract] [Full Text] [PDF]

				F. S. Willard, Z. Zheng, J. Guo, G. J. Digby, A. J. Kimple, J. M. Conley, C. A. Johnston, D. Bosch, M. D. Willard, V. J. Watts, et al. A Point Mutation to G{alpha}i Selectively Blocks GoLoco Motif Binding: DIRECT EVIDENCE FOR G{alpha}{middle dot}GoLoco COMPLEXES IN MITOTIC SPINDLE DYNAMICS J. Biol. Chem., December 26, 2008; 283(52): 36698 - 36710. [Abstract] [Full Text] [PDF]

				M. Kosloff, E. Alexov, V. Y. Arshavsky, and B. Honig Electrostatic and Lipid Anchor Contributions to the Interaction of Transducin with Membranes: MECHANISTIC IMPLICATIONS FOR ACTIVATION AND TRANSLOCATION J. Biol. Chem., November 7, 2008; 283(45): 31197 - 31207. [Abstract] [Full Text] [PDF]

				I. Iankova, C. Chavey, C. Clape, C. Colomer, N. C. Guerineau, N. Grillet, J.-F. Brunet, J.-S. Annicotte, and L. Fajas Regulator of G Protein Signaling-4 Controls Fatty Acid and Glucose Homeostasis Endocrinology, November 1, 2008; 149(11): 5706 - 5712. [Abstract] [Full Text] [PDF]

				F. Mir and G. C. Le Breton A Novel Nuclear Signaling Pathway for Thromboxane A2 Receptors in Oligodendrocytes: Evidence for Signaling Compartmentalization during Differentiation Mol. Cell. Biol., October 15, 2008; 28(20): 6329 - 6341. [Abstract] [Full Text] [PDF]

				L.-M. Fan, W. Zhang, J.-G. Chen, J. P. Taylor, A. M. Jones, and S. M. Assmann Abscisic acid regulation of guard-cell K+ and anion channels in G{beta}- and RGS-deficient Arabidopsis lines PNAS, June 17, 2008; 105(24): 8476 - 8481. [Abstract] [Full Text] [PDF]

				M. C. Theodoropoulou, P. G. Bagos, I. C. Spyropoulos, and S. J. Hamodrakas gpDB: a database of GPCRs, G-proteins, effectors and their interactions Bioinformatics, June 15, 2008; 24(12): 1471 - 1472. [Abstract] [Full Text] [PDF]

				A. Plagge, G. Kelsey, and E. L Germain-Lee Physiological functions of the imprinted Gnas locus and its protein variants G{alpha}s and XL{alpha}s in human and mouse J. Endocrinol., February 1, 2008; 196(2): 193 - 214. [Abstract] [Full Text] [PDF]

				D. Haasen, S. Merk, P. Seither, D. Martyres, S. Hobbie, and R. Heilker Pharmacological Profiling of Chemokine Receptor-Directed Compounds Using High-Content Screening J Biomol Screen, January 1, 2008; 13(1): 40 - 53. [Abstract] [PDF]

				S. C. Strickfaden and P. M. Pryciak Distinct Roles for Two G{alpha} G Interfaces in Cell Polarity Control by a Yeast Heterotrimeric G Protein Mol. Biol. Cell, January 1, 2008; 19(1): 181 - 197. [Abstract] [Full Text] [PDF]

				N. Makita, J. Sato, P. Rondard, H. Fukamachi, Y. Yuasa, M. A. Aldred, M. Hashimoto, T. Fujita, and T. Iiri Human Gs{alpha} mutant causes pseudohypoparathyroidism type Ia/neonatal diarrhea, a potential cell-specific role of the palmitoylation cycle PNAS, October 30, 2007; 104(44): 17424 - 17429. [Abstract] [Full Text] [PDF]

				M. E. Feigin and C. C. Malbon RGS19 regulates Wnt beta-catenin signaling through inactivation of G{alpha}o J. Cell Sci., October 1, 2007; 120(19): 3404 - 3414. [Abstract] [Full Text] [PDF]

				S.-H. Hsu and C.-W. Luo Molecular dissection of G protein preference using Gs{alpha} chimeras reveals novel ligand signaling of GPCRs Am J Physiol Endocrinol Metab, October 1, 2007; 293(4): E1021 - E1029. [Abstract] [Full Text] [PDF]

				V. Kerov, W. W. Rubin, M. Natochin, N. A. Melling, M. E. Burns, and N. O. Artemyev N-Terminal Fatty Acylation of Transducin Profoundly Influences Its Localization and the Kinetics of Photoresponse in Rods J. Neurosci., September 19, 2007; 27(38): 10270 - 10277. [Abstract] [Full Text] [PDF]

				M. Chisari, D. K. Saini, V. Kalyanaraman, and N. Gautam Shuttling of G Protein Subunits between the Plasma Membrane and Intracellular Membranes J. Biol. Chem., August 17, 2007; 282(33): 24092 - 24098. [Abstract] [Full Text] [PDF]

				D. K. Saini, V. Kalyanaraman, M. Chisari, and N. Gautam A Family of G Protein beta{gamma} Subunits Translocate Reversibly from the Plasma Membrane to Endomembranes on Receptor Activation J. Biol. Chem., August 17, 2007; 282(33): 24099 - 24108. [Abstract] [Full Text] [PDF]

				P. Kumar, Q. Wu, K. L. Chambliss, I. S. Yuhanna, S. M. Mumby, C. Mineo, G. G. Tall, and P. W. Shaul Direct Interactions with G{alpha}i and G{beta}{gamma} Mediate Nongenomic Signaling by Estrogen Receptor {alpha} Mol. Endocrinol., June 1, 2007; 21(6): 1370 - 1380. [Abstract] [Full Text] [PDF]

				S. Thiele, R. Werner, W. Ahrens, U. Hoppe, C. Marschke, P. Staedt, and O. Hiort A Disruptive Mutation in Exon 3 of the GNAS Gene with Albright Hereditary Osteodystrophy, Normocalcemic Pseudohypoparathyroidism, and Selective Long Transcript Variant Gs{alpha}-L Deficiency J. Clin. Endocrinol. Metab., May 1, 2007; 92(5): 1764 - 1768. [Abstract] [Full Text] [PDF]

				H.-J. Hippe, M. Luedde, S. Lutz, H. Koehler, T. Eschenhagen, N. Frey, H. A. Katus, T. Wieland, and F. Niroomand Regulation of Cardiac cAMP Synthesis and Contractility by Nucleoside Diphosphate Kinase B/G Protein {beta}{gamma} Dimer Complexes Circ. Res., April 27, 2007; 100(8): 1191 - 1199. [Abstract] [Full Text] [PDF]

				S. Basu, V. R. Jala, S. Mathis, S. T. Rajagopal, A. Del Prete, P. Maturu, J. O. Trent, and B. Haribabu Critical Role for Polar Residues in Coupling Leukotriene B4 Binding to Signal Transduction in BLT1 J. Biol. Chem., March 30, 2007; 282(13): 10005 - 10017. [Abstract] [Full Text] [PDF]

				Q. Zeng, X. Wang, and M. P. Running Dual Lipid Modification of Arabidopsis G{gamma}-Subunits Is Required for Efficient Plasma Membrane Targeting Plant Physiology, March 1, 2007; 143(3): 1119 - 1131. [Abstract] [Full Text] [PDF]

				M. L. Matsumoto, K. Narzinski, G. V. Nikiforovich, and T. J. Baranski A Comprehensive Structure-Function Map of the Intracellular Surface of the Human C5a Receptor: II. ELUCIDATION OF G PROTEIN SPECIFICITY DETERMINANTS J. Biol. Chem., February 2, 2007; 282(5): 3122 - 3133. [Abstract] [Full Text] [PDF]

				M. J. W. Adjobo-Hermans, J. Goedhart, and T. W. J. Gadella Jr Plant G protein heterotrimers require dual lipidation motifs of G{alpha} and G{gamma} and do not dissociate upon activation J. Cell Sci., December 15, 2006; 119(24): 5087 - 5097. [Abstract] [Full Text] [PDF]

				S. Offermanns Activation of Platelet Function Through G Protein-Coupled Receptors Circ. Res., December 8, 2006; 99(12): 1293 - 1304. [Abstract] [Full Text] [PDF]

				H. W. Tedford and G. W. Zamponi Direct G Protein Modulation of Cav2 Calcium Channels Pharmacol. Rev., December 1, 2006; 58(4): 837 - 862. [Abstract] [Full Text] [PDF]

				R. Herrmann, M. Heck, P. Henklein, K. P. Hofmann, and O. P. Ernst Signal Transfer from GPCRs to G Proteins: ROLE OF THE G{alpha} N-TERMINAL REGION IN RHODOPSIN-TRANSDUCIN COUPLING J. Biol. Chem., October 6, 2006; 281(40): 30234 - 30241. [Abstract] [Full Text] [PDF]

				L. N. Stemmle, T. A. Fields, and P. J. Casey The Regulator of G Protein Signaling Domain of Axin Selectively Interacts with G{alpha}12 but Not G{alpha}13 Mol. Pharmacol., October 1, 2006; 70(4): 1461 - 1468. [Abstract] [Full Text] [PDF]

				S. D. DePuy, J. Yao, C. Hu, W. McIntire, I. Bidaud, P. Lory, F. Rastinejad, C. Gonzalez, J. C. Garrison, and P. Q. Barrett The molecular basis for T-type Ca2+ channel inhibition by G protein beta2{gamma}2 subunits PNAS, September 26, 2006; 103(39): 14590 - 14595. [Abstract] [Full Text] [PDF]

				G. P. Prevost, M. O. Lonchampt, S. Holbeck, S. Attoub, D. Zaharevitz, M. Alley, J. Wright, M. C. Brezak, H. Coulomb, A. Savola, et al. Anticancer Activity of BIM-46174, a New Inhibitor of the Heterotrimeric G{alpha}/G{beta}{gamma} Protein Complex. Cancer Res., September 15, 2006; 66(18): 9227 - 9234. [Abstract] [Full Text] [PDF]

				G. L. Lukov, C. M. Baker, P. J. Ludtke, T. Hu, M. D. Carter, R. A. Hackett, C. D. Thulin, and B. M. Willardson Mechanism of Assembly of G Protein beta{gamma} Subunits by Protein Kinase CK2-phosphorylated Phosducin-like Protein and the Cytosolic Chaperonin Complex J. Biol. Chem., August 4, 2006; 281(31): 22261 - 22274. [Abstract] [Full Text] [PDF]

				A. Linglart, M. J. Mahon, M. A. Kerachian, D. M. Berlach, G. N. Hendy, H. Juppner, and M. Bastepe Coding GNAS Mutations Leading to Hormone Resistance Impair in Vitro Agonist- and Cholera Toxin-Induced Adenosine Cyclic 3',5'-Monophosphate Formation Mediated by Human XL{alpha}s Endocrinology, May 1, 2006; 147(5): 2253 - 2262. [Abstract] [Full Text] [PDF]

				N. Sanchez-Sanchez, L. Riol-Blanco, and J. L. Rodriguez-Fernandez The Multiple Personalities of the Chemokine Receptor CCR7 in Dendritic Cells J. Immunol., May 1, 2006; 176(9): 5153 - 5159. [Abstract] [Full Text] [PDF]

				S. Pandey, J.-G. Chen, A. M. Jones, and S. M. Assmann G-Protein Complex Mutants Are Hypersensitive to Abscisic Acid Regulation of Germination and Postgermination Development Plant Physiology, May 1, 2006; 141(1): 243 - 256. [Abstract] [Full Text] [PDF]

				T. M. Bonacci, J. L. Mathews, C. Yuan, D. M. Lehmann, S. Malik, D. Wu, J. L. Font, J. M. Bidlack, and A. V. Smrcka Differential targeting of Gbetagamma-subunit signaling with small molecules. Science, April 21, 2006; 312(5772): 443 - 446. [Abstract] [Full Text] [PDF]

				C.-S. Myung, W. K. Lim, J. M. DeFilippo, H. Yasuda, R. R. Neubig, and J. C. Garrison Regions in the G Protein {gamma} Subunit Important for Interaction with Receptors and Effectors Mol. Pharmacol., March 1, 2006; 69(3): 877 - 887. [Abstract] [Full Text] [PDF]

				A. M. D'Ursi, L. Giusti, S. Albrizio, F. Porchia, C. Esposito, G. Caliendo, C. Gargini, E. Novellino, A. Lucacchini, P. Rovero, et al. A Membrane-Permeable Peptide Containing the Last 21 Residues of the G{alpha}S Carboxyl Terminus Inhibits GS-Coupled Receptor Signaling in Intact Cells: Correlations between Peptide Structure and Biological Activity Mol. Pharmacol., March 1, 2006; 69(3): 727 - 736. [Abstract] [Full Text] [PDF]

				M. L. Bilodeau and H. E. Hamm Endothelial Nitric-Oxide Synthase Reveals a New Face in G Protein Signaling Mol. Pharmacol., March 1, 2006; 69(3): 677 - 679. [Abstract] [Full Text] [PDF]

				M. B. Tereshina, A. G. Zaraisky, and V. V. Novoselov Ras-dva, a member of novel family of small GTPases, is required for the anterior ectoderm patterning in the Xenopus laevis embryo Development, February 1, 2006; 133(3): 485 - 494. [Abstract] [Full Text] [PDF]

				L. H. Mayeenuddin, W. E. McIntire, and J. C. Garrison Differential Sensitivity of P-Rex1 to Isoforms of G Protein beta{gamma} Dimers J. Biol. Chem., January 27, 2006; 281(4): 1913 - 1920. [Abstract] [Full Text] [PDF]

				D. Dignard and M. Whiteway SST2, a Regulator of G-Protein Signaling for the Candida albicans Mating Response Pathway Eukaryot. Cell, January 1, 2006; 5(1): 192 - 202. [Abstract] [Full Text] [PDF]

				V. M. Tesmer, T. Kawano, A. Shankaranarayanan, T. Kozasa, and J. J. G. Tesmer Snapshot of Activated G Proteins at the Membrane: The G{alpha}q-GRK2-G{beta}{gamma} Complex Science, December 9, 2005; 310(5754): 1686 - 1690. [Abstract] [Full Text] [PDF]

				L. M Mehlmann Stops and starts in mammalian oocytes: recent advances in understanding the regulation of meiotic arrest and oocyte maturation Reproduction, December 1, 2005; 130(6): 791 - 799. [Abstract] [Full Text] [PDF]

				N. G. Abdulaev, T. Ngo, C. Zhang, A. Dinh, D. M. Brabazon, K. D. Ridge, and J. P. Marino Heterotrimeric G-protein {alpha}-Subunit Adopts a "Preactivated" Conformation When Associated with {beta}{gamma}-Subunits J. Biol. Chem., November 11, 2005; 280(45): 38071 - 38080. [Abstract] [Full Text] [PDF]

				N. Wettschureck and S. Offermanns Mammalian G Proteins and Their Cell Type Specific Functions Physiol Rev, October 1, 2005; 85(4): 1159 - 1204. [Abstract] [Full Text] [PDF]

				C. P D Wheeler-Jones Cell signalling in the cardiovascular system: an overview Heart, October 1, 2005; 91(10): 1366 - 1374. [Full Text] [PDF]

				T. Harashima and J. Heitman G{alpha} Subunit Gpa2 Recruits Kelch Repeat Subunits That Inhibit Receptor-G Protein Coupling during cAMP-induced Dimorphic Transitions in Saccharomyces cerevisiae Mol. Biol. Cell, October 1, 2005; 16(10): 4557 - 4571. [Abstract] [Full Text] [PDF]

				J.-A. Seo, K.-H. Han, and J.-H. Yu Multiple Roles of a Heterotrimeric G-Protein {gamma}-Subunit in Governing Growth and Development of Aspergillus nidulans Genetics, September 1, 2005; 171(1): 81 - 89. [Abstract] [Full Text] [PDF]

				S. A. Andric, D. Zivadinovic, A. E. Gonzalez-Iglesias, A. Lachowicz, M. Tomic, and S. S. Stojilkovic Endothelin-induced, Long Lasting, and Ca2+ Influx-independent Blockade of Intrinsic Secretion in Pituitary Cells by Gz Subunits J. Biol. Chem., July 22, 2005; 280(29): 26896 - 26903. [Abstract] [Full Text] [PDF]

				T. Kino, A. Tiulpakov, T. Ichijo, L. Chheng, T. Kozasa, and G. P. Chrousos G protein {beta} interacts with the glucocorticoid receptor and suppresses its transcriptional activity in the nucleus J. Cell Biol., June 20, 2005; 169(6): 885 - 896. [Abstract] [Full Text] [PDF]

				L. Wang, C. G. Radu, L. V. Yang, L. A. Bentolila, M. Riedinger, and O. N. Witte Lysophosphatidylcholine-induced Surface Redistribution Regulates Signaling of the Murine G Protein-coupled Receptor G2A Mol. Biol. Cell, May 1, 2005; 16(5): 2234 - 2247. [Abstract] [Full Text] [PDF]

				E. Kostenis, L. Martini, J. Ellis, M. Waldhoer, A. Heydorn, M. M. Rosenkilde, P. K. Norregaard, R. Jorgensen, J. L. Whistler, and G. Milligan A Highly Conserved Glycine within Linker I and the Extreme C Terminus of G Protein {alpha} Subunits Interact Cooperatively in Switching G Protein-Coupled Receptor-to-Effector Specificity J. Pharmacol. Exp. Ther., April 1, 2005; 313(1): 78 - 87. [Abstract] [Full Text] [PDF]

				W.-C. Chung and J. C. Kermode Suramin Disrupts Receptor-G Protein Coupling by Blocking Association of G Protein {alpha} and {beta}{gamma} Subunits J. Pharmacol. Exp. Ther., April 1, 2005; 313(1): 191 - 198. [Abstract] [Full Text] [PDF]

				D. Mielenz, C. Vettermann, M. Hampel, C. Lang, A. Avramidou, M. Karas, and H.-M. Jack Lipid Rafts Associate with Intracellular B Cell Receptors and Exhibit a B Cell Stage-Specific Protein Composition J. Immunol., March 15, 2005; 174(6): 3508 - 3517. [Abstract] [Full Text] [PDF]

				E. L. Riddle, R. A. Schwartzman, M. Bond, and P. A. Insel Multi-Tasking RGS Proteins in the Heart: The Next Therapeutic Target? Circ. Res., March 4, 2005; 96(4): 401 - 411. [Abstract] [Full Text] [PDF]

				B. N. Armbruster and B. L. Roth Mining the Receptorome J. Biol. Chem., February 18, 2005; 280(7): 5129 - 5132. [Full Text] [PDF]

				S. Krystofova and K. A. Borkovich The Heterotrimeric G-Protein Subunits GNG-1 and GNB-1 Form a G{beta}{gamma} Dimer Required for Normal Female Fertility, Asexual Development, and G{alpha} Protein Levels in Neurospora crassa Eukaryot. Cell, February 1, 2005; 4(2): 365 - 378. [Abstract] [Full Text] [PDF]

				K. R. Kerchner, R. L. Clay, G. McCleery, N. Watson, W. E. McIntire, C.-S. Myung, and J. C. Garrison Differential Sensitivity of Phosphatidylinositol 3-Kinase p110{gamma} to Isoforms of G Protein {beta}{gamma} Dimers J. Biol. Chem., October 22, 2004; 279(43): 44554 - 44562. [Abstract] [Full Text] [PDF]

				I. D. Alves, K. A. Ciano, V. Boguslavski, E. Varga, Z. Salamon, H. I. Yamamura, V. J. Hruby, and G. Tollin Selectivity, Cooperativity, and Reciprocity in the Interactions between the {delta}-Opioid Receptor, Its Ligands, and G-proteins J. Biol. Chem., October 22, 2004; 279(43): 44673 - 44682. [Abstract] [Full Text] [PDF]

				L. Bogdanik, R. Mohrmann, A. Ramaekers, J. Bockaert, Y. Grau, K. Broadie, and M.-L. Parmentier The Drosophila Metabotropic Glutamate Receptor DmGluRA Regulates Activity-Dependent Synaptic Facilitation and Fine Synaptic Morphology J. Neurosci., October 13, 2004; 24(41): 9105 - 9116. [Abstract] [Full Text] [PDF]

				M. B. Jones, D. P. Siderovski, and S. B. Hooks The G{beta}{gamma} DIMER as a NOVEL SOURCE of SELECTIVITY in G-Protein Signaling: GGL-ing AT CONVENTION Mol. Interv., August 1, 2004; 4(4): 200 - 214. [Abstract] [Full Text] [PDF]

				N. A. Eckardt Abscisic Acid Signal Transduction: Function of G Protein-Coupled Receptor 1 in Arabidopsis PLANT CELL, June 1, 2004; 16(6): 1353 - 1354. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cabrera-Vera, T. M. Articles by Hamm, H. E. Search for Related Content PubMed PubMed Citation Articles by Cabrera-Vera, T. M. Articles by Hamm, H. E. Pubmed/NCBI databases Substance via MeSH