Unravelling principles underlying neurotransmitter release are key to understand neural signaling. Here, we describe how surface mobility of voltage-dependent calcium channels (VDCCs) modulates release probabilities (P-r) of synaptic vesicles (SVs). Coupling distances of <10 to >100 nm have been reported for SVs and VDCCs in different synapses. Tracking individual VDCCs revealed that within hippocampal synapses, similar to 60% of VDCCs are mobile while confined to presynaptic membrane compartments. Intracellular Ca2+ chelation decreased VDCC mobility. Increasing VDCC surface populations by co-expression of the alpha 2 delta 1 subunit did not alter channel mobility but led to enlarged active zones (AZs) rather than higher channel densities. VDCCs thus scale presynaptic scaffolds to maintain local mobility. We propose that dynamic coupling based on mobile VDCCs supports calcium domain co-operativity and tunes neurotransmitter release by equalizing P-r for docked SVs within AZs.
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