Distinct domains of Complexin I differentially regulate neurotransmitter release

Complexins constitute a family of four synaptic high-affinity SNARE complex binding proteins. They positively regulate a late, post-priming step in Ca(2+)-triggered synchronous neurotransmitter release, but the underlying molecular mechanisms are unclear. We show here that SNARE complex binding of Complexin I via its central α-helix is necessary but unexpectedly not sufficient for its key function in promoting neurotransmitter release. An accessory α-helix N-terminal of the SNARE complex binding region plays an inhibitory role in fast synaptic exocytosis, while its N-terminally adjacent sequences facilitate Ca(2+)-triggered release even in the absence of the Ca(2+) sensor Synaptotagmin 1. Our results indicate that distinct functional domains of Complexins differentially regulate synaptic exocytosis, and that via the interplay between these domains Complexins play a crucial role in fine-tuning Ca(2+)-triggered fast neurotransmitter release.