The Molecular Mechanisms Underlying the Regulation of the Biological Activity of Corticotropin-Releasing Hormone Receptors: Implications for Physiology and Pathophysiology
Edward W. Hillhouse and
Dimitris K. Grammatopoulos
The Leeds Institute of Genetics, Health and Therapeutics (E.W.H.), The University of Leeds, Leeds LS2 9NL, United Kingdom; and Department of Endocrinology and Metabolism (D.K.G.), Warwick Medical School, The University of Warwick, Coventry CV4 7AL, United Kingdom
Correspondence: Address all correspondence and requests for reprints to: Edward W. Hillhouse, The Leeds Institute of Genetics, Health and Therapeutics, The University of Leeds, Leeds LS2 9NL, United Kingdom. E-mail: e.w.hillhouse{at}leeds.ac.uk; or Dimitris K. Grammatopoulos, Endocrinology and Metabolism, Warwick Medical School, The University of Warwick, Coventry CV4 7AL, United Kingdom. E-mail: d.grammatopoulos{at}warwick.ac.uk.
The CRH receptor (CRH-R) is a member of the secretin familyof G protein-coupled receptors. Wide expression of CRH-Rs inthe central nervous system and periphery ensures that theircognate agonists, the family of CRH-like peptides, are capableof exerting a wide spectrum of actions that underpin their criticalrole in integrating the stress response and coordinating theactivity of fundamental physiological functions, such as theregulation of the cardiovascular system, energy balance, andhomeostasis. Two types of mammal CRH-R exist, CRH-R1 and CRH-R2,each with unique splicing patterns and remarkably distinct pharmacologicalproperties, but similar signaling properties, probably reflectingtheir distinct and sometimes contrasting biological functions.The regulation of CRH-R expression and activity is not fullyelucidated, and we only now begin to fully understand the impacton mammalian pathophysiology. The focus of this review is thecurrent and evolving understanding of the molecular mechanismscontrolling CRH-R biological activity and functional flexibility.This shows notable tissue-specific characteristics, highlightedby their ability to couple to distinct G proteins and activatetissue-specific signaling cascades. The type of activating agonist,receptor, and target cell appears to play a major role in determiningthe overall signaling and biological responses in health anddisease.
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