Molecular basis for N-type voltage-gated Ca2+ channel modulation by Gq protein-coupled receptors

N-type voltage-gated Ca 2+ (Ca V 2.2) channels, which enable synaptic transmission by triggering neurotransmitter release, are tightly modulated by G protein-coupled receptors (GPCRs) via several downstream signaling messengers, such as Gbg, calmodulin, arachidonic acid and PIP 2 . However, the molecular mechanism by which G q/11 -coupled receptors (G q PCRs) suppress Ca V 2.2 currents remains unclear. In this research highlight, we review our recent finding that M 1 muscarinic receptors inhibit Ca V 2.2 channels through both Gbg-mediated voltage-dependent (VD) and Gα q/11 /PLC-mediated voltage-independent (VI) pathways. Our photometry results also demonstrate that Gbg-mediated VD inhibition of Ca V 2.2 channels initiates approximately 3s earlier than VI inhibition, and is strongly potentiated in cells expressing plasma membrane-localized Ca V b subunits. Our observations demonstrate a novel mechanism for Ca V 2.2 channel modulation by G q PCRs where the subcellular location of Ca V b subunits plays a critical role in determining the voltage-dependence of current suppression by M 1 receptors.