Decoding Calcium Signals - Synaptotagmin Isoforms and Dynamics of Neurotransmitter Release
Yale Nanobiology Institute 1 , Department of Neurology 2 , Yale University, New Haven, CT, USA.
Synapses in the nervous system release neurotransmitters from synaptic vesicles in response to presynaptic Ca²⁺ signal with remarkable precision. Yet, this process exhibits considerable variability in the timing of individual vesicle fusion events and in how synapses respond to recent patterns of activity. This heterogeneity is essential for information processing in the brain, but its molecular underpinnings remain unclear. Current models suggest that this diversity arises from the interplay between presynaptic Ca²⁺ dynamics and multiple Ca²⁺ sensors with distinct molecular properties. To explore this, we combined reconstituted functional assays with structural biology and computational modeling to examine how the ‘fast’ release sensor Synaptotagmin-1 (Syt1) and the ‘slow’ release sensor Synaptotagmin-7 (Syt7) regulate vesicle fusion dynamics. We found that Syt1 and Syt7, together with SNARE proteins and Complexin, are necessary and sufficient to reproduce the full spectrum of Ca²⁺-evoked release kinetics and activity-dependent plasticity. Our data indicate that Syt1 and Syt7 compete for binding to the same SNARE complex, and the distinct Ca²⁺/SNARE-binding properties of their individual C2 domains shape the overall kinetics of vesicle fusion. These findings provide critical insight into how a small set of proteins enables nerve terminals to adapt and regulate Ca²⁺-evoked neurotransmitter release, thereby meeting diverse functional demands.