Ca²⁺-Independent Exocytosis Favors Axonal Release through Enlarged Fusion Pores in Sensory Neurons

While Katz’s Ca²⁺ hypothesis has defined that action potentials trigger neurotransmitter release through Ca²⁺-dependent secretion (CDS), recent discoveries of Ca²⁺-independent secretion (CiVDS) have demonstrated that action potentials per se can directly trigger exocytosis independent of Ca²⁺. However, a critical gap remains regarding how CDS and CiVDS coordinate to precisely control neurotransmitter release within a single neuron’s soma and axons/terminals. Here, using high-resolution live imaging, we simultaneously visualized single-vesicle release in the somata and axons/terminals of individual dorsal root ganglion (DRG) neurons and show that: (1) CiVDS and CDS co-exist in both somatic and axonal regions; (2) the release probability of CiVDS in axons is ~2-fold higher than in somata; (3) CiVDS accounts for > 60% of total axonal release; (4) CiVDS favors full fusion-like quantal release while CDS favors kiss-and-run sub-quantal release. These findings suggest a more profound contribution of CiVDS than CDS in axonal neurotransmission in sensory DRG neurons.