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Department of Pharmacology, University College London, London, United Kingdom
Calcium influx into any cell requires fine tuning to guarantee the correct balance between activation of calcium-dependent processes, such as muscle contraction and neurotransmitter release, and calcium-induced cell damage. G protein-coupled receptors play a critical role in negative feedback to modulate the activity of the CaV2 subfamily of the voltage-dependent calcium channels, which are largely situated on neuronal and neuro-endocrine cells. The basis for the specificity of the relationships among membrane receptors, G proteins, and effector calcium channels will be discussed, as well as the mechanism by which G protein-mediated inhibition is thought to occur. The inhibition requires free G
Abstract I. Introduction A. Molecular Subtypes of Calcium Channel II. Role of CaV{beta} Subunits in Calcium Channel Function A. Binding of CaV{beta} to the {alpha}1 I-II Linker B. Binding of CaV{beta} Subunits to the N and C Termini of CaV{alpha}1 Subunits III. Modulation of Calcium Channels IV. Inhibitory Coupling between G Proteins and Voltage-Gated Calcium Channels in Native Tissue A. The G Protein Subunits Involved in the Direct Inhibitory Modulation of Native and Heterologously Expressed Calcium Channels B. Voltage Dependence of G Protein Modulation of Calcium Channels C. The Role of the CaV{alpha}1 I-II Linker in G Protein Modulation of CaV2 Calcium Channels D. The Essential Role of the CaV{alpha}1 N Terminus in G Protein Modulation E. Basis for the Selectivity of Calcium Current Inhibition by Transmembrane G Protein-Coupled Receptors F. Is There a Role for the C Terminus in Calcium Current Inhibition by G Protein-Coupled Receptors? V. Essential Role of Cav{beta} Subunits in G Protein Modulation of Calcium Channels A. Initial Evidence for the Role of CaV{beta} Subunits in G Protein Modulation in Native Neurons B. The Involvement of CaV{beta} Subunits in G Protein Inhibition of Heterologously Expressed Calcium Channels C. Does G{beta}{gamma} Displace CaV{beta} Subunits? D. Potential Overlap of Determinants for CaV{beta} Subunit and G{beta}{gamma} Subunit Function VI. Molecular Mechanism of G Protein-Mediated Inhibition VII. Recovery from G Protein-Mediated Inhibition VIII. Conclusion
dimers, and the cytoplasmic linker between domains I and II of the CaV2 
1 subunits binds G dimers, whereas the intracellular N terminus of CaV2 1 subunits provides essential determinants for G protein modulation. Evidence suggests a key role for the subunits of calcium channels in the process of G protein modulation, and the role of a class of proteins termed "regulators of G protein signaling" will also be described.
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