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

摘要

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.