Synaptotagmin I functions as a calcium regulator of release probability

In all synapses, Ca2+ triggers neurotransmitter release to initiate signal transmission. Ca2+ presumably acts by activating synaptic Ca2+ sensors, but the nature of these sensors-which are the gatekeepers to neurotransmission -remains unclear. One of the candidate Ca2+ sensors in release is the synap tic Ca2+-binding protein synaptotagmin I. Here we have studied a point muta tion in synaptotagmin I that causes a twofold decrease in overall Ca2+ affi nity without inducing structural or conformational changes. When introduced by homologous recombination into the endogenous synaptotagmin I gene in mi ce, this point mutation decreases the Ca2+ sensitivity of neurotransmitter release twofold, but does not alter spontaneous release or the size of the readily releasable pool of neurotransmitters. Therefore, Ca2+ binding to sy naptotagmin I participates in triggering neurotransmitter release at the sy napse.