Molecular mechanisms governing Ca2+ regulation of evoked and spontaneous release

The relationship between transmitter release evoked by action potentials and spontaneous release has fascinated neuroscientists for half a century, and separate biological roles for spontaneous release are emerging. Nevertheless, separate functions for spontaneous and Ca2+-evoked release do not necessarily indicate different origins of these two manifestations of vesicular fusion. Here we review how Ca2+ regulates evoked and spontaneous release, emphasizing that Ca2+ can briefly increase vesicle fusion rates one-millionfold above spontaneous rates. This high dynamic range suggests that docked and readily releasable pool (RRP) vesicles might be protected against spontaneous release while also being immediately available for ultrafast Ca2+-evoked release. Molecular mechanisms for such release clamping of highly fusogenic RRP vesicles are increasingly investigated. Thus, we view spontaneous release as a consequence of the highly release-competent state of a standing pool of RRP vesicles, which is molecularly fine-tuned to control spontaneous release.