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Molecular Biology of Adenosine Triphosphate-Sensitive Potassium Channels¹

Departments of Medicine (L.A.-B.) and Cell Biology (J.B.), Baylor College of Medicine, Houston, Texas 77030

I. Introduction

II. How Are K_ATP Channels Defined?

III. How Do K_ATP Channels Affect the Membrane Potential of Pancreatic ß-Cells?

IV. K_ATP Channel Subunits

A. The K_IR family of inwardly rectifying K+ channels

B. Sulfonylurea receptors

V. Reconstitution of K_ATP Channel Activity from SUR1 and K_IR6.2

A. The question of "promiscuous coupling" of SUR1 with other inward rectifiers

VI. K_ATP Channel Structure

A. K_IR6.2 forms the pore of a K_ATP channel

B. SUR1 and K_IR6.x are physically associated

C. Coexpression with K_IR6.2 affects the maturation of SUR1

D. Complex glycosylated SUR1 and K_IR6.2 assemble a large multimer

E. A 1:1 stoichiometry of SUR to K_IR is both necessary and sufficient to make K_ATP channels

F. Other K_IR channels are tetramers

G. The stoichiometry of active ß-cell K_ATP channels is (SUR1/K_IR6.2)₄

VII. Regulation of K_ATP Channel Activity

A. How do ATP and ADP exert their effects on K_ATP channels?

B. Where are the nucleotide binding sites located?

C. C-terminally truncated K_IR6.2 channels show abnormal kinetics

D. Coexpression of K_IR6.2C subunits with SUR restores normal K_ATP channel activity

E. Why are K_IR6.2 channels silent?

F. The N terminus of K_IR6.2 limits burst duration

G. Where do the openers bind and how do they work?

H. Do SURs have adenosine triphosphatase (ATPase) activity?

I. Do SURs have transport activity?

J. Is there an endogenous substrate?

VIII. Human SUR1 and K_IR6.2 Genes

IX. K_ATP Channels and Persistent Hyperinsulinemic Hypoglycemia of Infancy (PHHI)

A. HI-GK

B. HI-GlnDH

C. HI-"unknown"

D. HI-K_IR6.2

E. HI-SUR1

X. Linking PHHI to Defects in K_ATP Channel Activity

A. ß-Cells from newborns diagnosed with "sporadic" PHHI lack K_ATP channel activity

B. PHHI ß-cells with the SUR1 exon 35 mutation lack K_ATP channel activity

C. Why is there a lack of dominant negative mutations?

D. Development of mouse models

XI. Other Issues

A. Nesidioblastosis does not cause PHHI

B. "Diffuse" vs. "focal" forms of PHHI

XII. K_ATP and Non-Insulin-Dependent Diabetes Mellitus (NIDDM)

A. ß-Cell type K_ATP channels in the brain

XIII. The Leptin Connection

XIV. Summary and Conclusions

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