G protein modulation of voltage-gated calcium channels.

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 beta gamma dimers, and the cytoplasmic linker between domains I and II of the CaV2 alpha 1 subunits binds G beta gamma dimers, whereas the intracellular N terminus of CaV2 alpha 1 subunits provides essential determinants for G protein modulation. Evidence suggests a key role for the beta 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.