Abstract

Neurotransmitters stored in synaptic vesicles at nerve endings are synchronously released in less than one millisecond after the action potential arrives and calcium ions secondarily enter the pre-synaptic cytoplasm.  This is by far the fastest membrane fusion mechanism in nature, as is required for all thought and action.  Yet, neurotransmission relies on the same SNAR Epin zippering mechanism that powers more leisurely and less coherent hormone release and vesicle trafficking within the cell.  How can the same molecular machine provide for such action on time scales differing by up to a factor of 10,000?  Answers are emerging from mechanistic studies of the two key elements of synaptic regulatory machinery that together allow many SNAR Epins to synchronize spatially and temporally.  The calcium sensor, Synaptotagmin, assembles into rings that can impede fusion until they disassemble upon binding calcium ions.  The rod-like Complexin molecule can organize two layers of SNAR Epins into zig-zag arrays while at the same time impeding completion of zippering.