Presynaptic terminals favor intermediate-conductance Ca V2.2 (N type) over high-conductance Ca V 1 (L type) channels for single-channel, Ca2+ nanodomain-triggered synaptic vesicle fusion. However, the standard Ca V 1>Ca V 2>Ca V 3 conductance hierarchy is based on recordings using nonphysiological divalent ion concentrations. We found that, with physiological Ca2+ gradients, the hierarchy was Ca V 2.2>Ca V 1>Ca V 3. Mathematical modeling predicts that the Ca V 2.2 Ca2+ nanodomain, which is ĝ̂1/425% more extensive than that generated by Ca V 1, can activate a calcium-fusion sensor located on the proximal face of the synaptic vesicle.
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