Synaptotagmin I functions as a calcium regulator of release probability

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.