In all synapses, Ca 2+ triggers neurotransmitter release to initiate signal transmission. Ca 2+ presumably acts by activating synaptic Ca 2+ sensors, but the nature of these sensors - which are the gatekeepers to neurotransmission - remains unclear. One of the candidate Ca 2+ sensors in release is the synaptic Ca 2+-binding protein synaptotagmin I. Here we have studied a point mutation in synaptotagmin I that causes a twofold decrease in overall Ca 2+ affinity without inducing structural or conformational changes. When introduce by homologous recombination into the endogenous synaptotagmin I gene in mice, this point mutation decreases the Ca 2+ sensitivity of neurotransmitter release twofold, but does not alter spontaneous release or the size of the readily releasable pool of neurotransmitters. Therefore, Ca 2+ binding to synaptotagmin I participates in triggering neurotransmitter release at the synapse.
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