Ca²⁺-independent but voltage-dependent quantal catecholamine secretion (CiVDS) in the mammalian sympathetic nervous...

Action potential-induced vesicular exocytosis is considered exclusively Ca²⁺ dependent in Katz's Ca²⁺ hypothesis on synaptic transmission. This long-standing concept gets an exception following the discovery of Ca²⁺-independent but voltage-dependent secretion (CiVDS) and its molecular mechanisms in dorsal root ganglion sensory neurons. However, whether CiVDS presents only in sensory cells remains elusive. Here, by combining multiple independent recordings, we report that [1] CiVDS robustly presents in the sympathetic nervous system, including sympathetic superior cervical ganglion neurons and slice adrenal chromaffin cells, [2] uses voltage sensors of Ca²⁺ channels (N-type and novel L-type), and [3] contributes to catecholamine release in both homeostatic and fight-or-flight like states; [4] CiVDS-mediated catecholamine release is faster than that of Ca²⁺-dependent secretion at the quantal level and [5] increases Ca²⁺ currents and contractility of cardiac myocytes. Together, CiVDS presents in the sympathetic nervous system with potential physiological functions, including cardiac muscle contractility.