Control of Ca_V2 calcium channels and neurosecretion by heterotrimeric G protein coupled receptors

Ca_V2.1 (P/Q-type) and Ca_V2.2 (N-type) voltage-gated Ca²⁺ channels play pivotal roles in synaptic transmission and neuroendocrine hormone secretion by coupling excitation (i.e. action potential firing) to transmitter release through Ca²⁺-dependent exocytosis. Consequently, multiple protein-protein interactions and cell signaling pathways converge on these channels to precisely control the amount, location, and timing of Ca²⁺ entry. Among these, G protein coupled receptors (GPCRs) respond to autocrine, paracrine, and retrograde chemical signals to provide important feedback regulation. Several distinct signaling pathways recruited by GPCRs can converge on Ca²⁺ channels, however this chapter focuses on the so-called voltage-dependent inhibition mediated by direct binding of G protein βγ subunits (Gβγ) to the channels. This includes an overview of the functional impact of Gβγ on Ca_V2 channels and current understanding of the molecular mechanisms involved. Neuroendocrine chromaffin cells are also highlighted as both a physiologically important system and powerful cellular model to investigate modulation of Ca²⁺ channels and neurosecretion by GPCRs.