N-type [Ca.sup.2+] channels carry the largest current: implications for nanodomains and transmitter release

Presynaptic terminals favor intermediate-conductance [Ca.sub.V]2.2 (N type) over high-conductance [Ca.sub.V]1 (L type) channels for single-channel, [Ca.sup.2+] nanodomain-triggered synaptic vesicle fusion. However, the standard [Ca.sub.V]1>[Ca.sub.V]2>[Ca.sub.V]3 conductance hierarchy is based on recordings using nonphysiological divalent ion concentrations. We found that, with physiological [Ca.sup.2+] gradients, the hierarchy was [Ca.sub.V]2.2>[Ca.sub.V]1>[Ca.sub.V]3. Mathematical modeling predicts that the [Ca.sub.V]2.2 [Ca.sup.2+] nanodomain, which is ~25% more extensive than that generated by [Ca.sub.V]1, can activate a calcium-fusion sensor located on the proximal face of the synaptic vesicle.