Calcium Sensors of Neurotransmitter Release

Calcium (Ca²⁺) plays a critical role in triggering all three primary modes of neurotransmitter release (synchronous, asynchronous, and spontaneous). Synaptotagmin1, a protein with two C2 domains, is the first isoform of the synaptotagmin family that was identified and demonstrated as the primary Ca²⁺ sensor for synchronous neurotransmitter release. Other isoforms of the synaptotagmin family as well as other C2 proteins such as the double C2 domain protein family were found to act as Ca²⁺ sensors for different modes of neurotransmitter release. Major recent advances and previous data suggest a new model, release-of-inhibition, for the initiation of Ca²⁺-triggered synchronous neurotransmitter release. Synaptotagmin1 binds Ca²⁺ via its two C2 domains and relieves a primed pre-fusion machinery. Before Ca²⁺ triggering, synaptotagmin1 interacts Ca²⁺ independently with partially zippered SNARE complexes, the plasma membrane, phospholipids, and other components to form a primed pre-fusion state that is ready for fast release. However, membrane fusion is inhibited until the arrival of Ca²⁺ reorients the Ca²⁺-binding loops of the C2 domain to perturb the lipid bilayers, help bridge the membranes, and/or induce membrane curvatures, which serves as a power stroke to activate fusion. This chapter reviews the evidence supporting these models and discusses the molecular interactions that may underlie these abilities.