CaV2.2 Gates Calcium-Independent but Voltage-Dependent Secretion in Mammalian Sensory Neurons

Abstract

Action potential induces membrane depolarization and triggers intracellular free Ca2+ concentration (Ca2+)-dependent secretion (CDS) via Ca2+ influx through voltage-gated Ca2+ channels. We report a new type of somatic exocytosis triggered by the action potential per se—Ca2+-independent but voltage-dependent secretion (CiVDS)—in dorsal root ganglion neurons. Here we uncovered the molecular mechanism of CiVDS, comprising a voltage sensor, fusion machinery, and their linker. Specifically, the voltage-gated N-type Ca2+ channel (CaV2.2) is the voltage sensor triggering CiVDS, the SNARE complex functions as the vesicle fusion machinery, the “synprint” of CaV2.2 serves as a linker between the voltage sensor and the fusion machinery, and ATP is a cargo of CiVDS vesicles. Thus, CiVDS releases ATP from the soma while CDS releases glutamate from presynaptic terminals, establishing the CaV2.2-SNARE “voltage-gating fusion pore” as a novel pathway co-existing with the canonical “Ca2+-gating fusion pore” pathway for neurotransmitter release following action potentials in primary sensory neurons. Chai et al. uncover the molecular mechanism and cargo of Ca2+-independent but voltage-dependent secretion (CiVDS). In addition to triggering secretion by Ca2+ influx, the N-type Ca2+ channel gates CiVDS through binding the vesicular fusion machinery for ATP release in pain-sensing neurons.