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

Abstract

N-type voltage-gated Ca²⁺ (Ca_V2.2) 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 PIP₂. However, the molecular mechanism by which G_q/11-coupled receptors (G_qPCRs) suppress Ca_V2.2 currents remains unclear. In this research highlight, we review our recent finding that M₁ muscarinic receptors inhibit Ca_V2.2 channels through both Gbg-mediated voltage-dependent (VD) and G?_q/11/PLC-mediated voltage-independent (VI) pathways. Our photometry results also demonstrate that Gbg-mediated VD inhibition of Ca_V2.2 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_V2.2 channel modulation by G_qPCRs where the subcellular location of Ca_V b subunits plays a critical role in determining the voltage-dependence of current suppression by M₁ receptors.