Signaling role of the voltage-gated calcium channel as the molecular on/off-switch of secretion.

Voltage-gated calcium channels (VGCC) are involved in a large variety of cellular Ca(2+) signaling processes, including exocytosis, a Ca(2+) dependent release of neurotransmitters and hormones. Great progress has been made in understanding the mode of action of VGCC in exocytosis, a process distinguished by two sequential yet independent Ca(2+) binding reactions. First, Ca(2+) binds at the selectivity filter, the EEEE motif of the VGCC, and second, subsequent to a brief and intense Ca(2+) inflow to synaptotagmin, a vesicular protein. Inquiry into the functional and physical interactions of the channels with synaptic proteins has demonstrated that exocytosis is triggered during the initial Ca(2+) binding at the channel pore, prior to Ca(2+) entry. Accordingly, a cycle of secretion begins by an incoming stimulus that releases vesicles from a releasable pool upon Ca(2+) binding at the pore, and at the same time, the transient increase in [Ca(2+)](i) primes a fresh set of non-releasable vesicles, to be fused by the next incoming stimulus. We propose a model, in which the Ca(2+) binding at the EEEE motif and the consequent conformational changes in the channel are the primary event in triggering secretion, while synaptotagmin acts as a vesicle docking protein. Thus, the channel serves as the molecular On/Off signaling switch, where the predominance of a conformational change in Ca(2+)-bound channel provides for the fast secretory process.

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