Ca_V2.2 Gates Calcium-Independent but Voltage-Dependent Secretion in Mammalian Sensory Neurons

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 (Ca_V2.2) is the voltage sensor triggering CiVDS, the SNARE complex functions as the vesicle fusion machinery, the “synprint” of Ca_V2.2 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 Ca_V2.2-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.