Regulating Quantal Size of Neurotransmitter Release through a GPCR Voltage Sensor

Abstract

Current models emphasize that membrane voltage (Vm) depolarization-induced Ca2+ influx triggers the fusion of vesicles to the plasma membrane. In sympathetic adrenal chromaffin cells, activation of a variety of G-protein coupled receptors (GPCRs) can inhibit quantal size (QS) through the direct interaction of G-protein Giβγ subunits with exocytosis fusion proteins. Here we report that, independently from Ca2+, Vm (action potential) per se regulates the amount of catecholamine released from each vesicle, the QS. The Vm regulation of QS was through ATP-activated GPCR-P2Y12 receptors. D76 and D127 in P2Y12 were the voltage-sensing sites. Finally, we revealed the relevance of the Vm-dependence of QS for tuning auto-inhibition and target cell functions. Together, membrane voltage per se increases the quantal size of dense-core vesicle release of catecholamine via Vm P2Y12(D76/D127) Giβγ QS myocyte contractility, offering an universal Vm-GPCR-signaling pathway for their functions in the nervous system and other systems containing GPCRs. Supported by grants from NSFC, MOST and the CLS-program.