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Article

Direct G Protein Modulation of Ca_v2 Calcium Channels

Hotchkiss Brain Institute, Department of Physiology and Biophysics, University of Calgary, Calgary, Canada

Abstract

I. Introduction

II. Molecular Structure and Distributions of Voltage-Gated Calcium Channels

A. alpha1 Subunit

B. Ancillary Calcium Channel Subunits

III. G Protein-Coupled Receptor Signaling—A Brief Overview

A. Activation of G Proteins via G Protein-Coupled Receptors

B. Subtypes of G Protein Subunits

C. Regulation of G Protein Activity

D. Receptor Desensitization and Internalization

IV. Discovery and Characterization of Direct G Protein Inhibition of Cav2 Calcium Channels

A. Electrophysiological Hallmarks of Direct G Protein Inhibition

B. Does the Nature of the Galpha Subunit Affect Voltage-Dependent Modulation?

C. Voltage-Independent G Protein Inhibition

D. Regulator of G Protein Signaling and Activator of G Protein Signaling Proteins and Calcium Channel Inhibition

V. Calcium Channel Structural Determinants of G Protein Modulation

A. Calcium Channel alpha1 Subunit Structural Determinants

B. Role of the Calcium Channel beta Subunit

VI. Modulation of G Protein Modulation

A. Cross-Talk between G Protein Inhibition and Protein Kinase C Modulation

B. Synaptic Proteins

VII. G Protein Structural Determinants of N-Type Channel Modulation

A. Gbeta Subtype Dependence

B. Gbeta Structural Determinants

C. Ggamma Subtype Dependence

VIII. Signaling Complexes Involving N-Type Channels and G Protein-Coupled Receptors

IX. Concluding Remarks

The regulation of presynaptic, voltage-gated calcium channels by activation of heptahelical G protein-coupled receptors exerts a crucial influence on presynaptic calcium entry and hence on neurotransmitter release. Receptor activation subjects presynaptic N- and P/Q-type calcium channels to a rapid, membrane-delimited inhibition—mediated by direct, voltage-dependent interactions between G protein subunits and the channels—and to a slower, voltage-independent modulation involving soluble second messenger molecules. In turn, the direct inhibition of the channels is regulated as a function of many factors, including channel subtype, ancillary calcium channel subunits, and the types of G proteins and G protein regulatory factors involved. Twenty-five years after this mode of physiological regulation was first described, we review the investigations that have led to our current understanding of its molecular mechanisms.

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