G protein inhibition of CaV2 calcium channels

Voltage-gated Ca2+ channels translate the electrical inputs of excitable cells into biochemical outputs by controlling influx of the ubiquitous second messenger Ca2+. As such the channels play pivotal roles in many cellular functions including the triggering of neurotransmitter and hormone release by Ca(V)2.1 (P/Q-type) and Ca(V)2.2 (N-type) channels. It is well established that G protein coupled receptors (GPCRs) orchestrate precise regulation neurotransmitter and hormone release through inhibition of Ca(V)2 channels. Although the GPCRs recruit a number of different pathways, perhaps the most prominent, and certainly most studied among these is the so-called voltage-dependent inhibition mediated by direct binding of G beta gamma to the alpha(1) subunit of Ca(V)2 channels. This article will review the basics of Ca2+-channels and G protein signaling, and the functional impact of this now classical inhibitory mechanism on channel function. It will also provide an update on more recent developments in the field, both related to functional effects and crosstalk with other signaling pathways, and advances made toward understanding the molecular interactions that underlie binding of G beta gamma to the channel and the voltage-dependence that is a signature characteristic of this mechanism.