N-type voltage-gated Ca2+ (CaV2.2) 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 Gq/11-coupled receptors (GqPCRs) suppress CaV2.2 currents remains unclear. In this research highlight, we review our recent finding that M1 muscarinic receptors inhibit CaV2.2 channels through both Gbg-mediated voltage-dependent (VD) and Gαq/11/PLC-mediated voltage-independent (VI) pathways. Our photometry results also demonstrate that Gbg-mediated VD inhibition of CaV2.2 channels initiates approximately 3s earlier than VI inhibition, and is strongly potentiated in cells expressing plasma membrane-localized CaV b subunits. Our observations demonstrate a novel mechanism for CaV2.2 channel modulation by GqPCRs where the subcellular location of CaV b subunits plays a critical role in determining the voltage-dependence of current suppression by M1 receptors.