Synaptotagmin · Grey Matter

Synaptotagmin is the calcium sensor on the synaptic vesicle: when calcium floods in after a spike it binds this protein, and synaptotagmin triggers the final fusion that the SNARE complex has prepared, so release happens within a fraction of a millisecond of the spike.

Synaptotagmin. Synaptotagmin is the calcium sensor on the synaptic vesicle: when calcium floods in after a spike it binds this protein, and synaptotagmin triggers the final fusion that the SNARE complex has prepared, so release happens within a fraction of a millisecond of the spike.

Synaptotagmin-1, the main fast sensor in the forebrain, is anchored in the vesicle membrane and carries two calcium-binding modules (the C2A and C2B domains), each with a pocket lined by negatively charged aspartates. Calcium binding lets these domains plunge into the terminal's membrane and push on the half-zipped SNAREs, which completes fusion. Because several calcium ions must bind for a vesicle to go, release rises steeply with calcium, close to the fourth power of its concentration.

It synchronises release. In neurons without synaptotagmin-1 the spike-locked burst of release almost disappears, while slower, scattered (asynchronous) release remains; a different, slower sensor (synaptotagmin-7) handles much of that and contributes to facilitation.

It also clamps. Without its calcium-bound signal synaptotagmin helps hold primed vesicles back, so spontaneous fusion at rest stays rare.

Its steepness explains the power of small calcium changes: a presynaptic receptor that trims calcium entry by a fifth cuts release by more than half.

Synaptotagmin is the trigger, the SNAREs are the spring.

The SNAREs store the energy for fusion; synaptotagmin decides the moment, and its need for several calcium ions makes that moment sharp.

Questions: Why do some synapses grow stronger during a burst while others grow weaker? It depends mostly on how likely the synapse is to release at the first spike. A synapse with a low release probability keeps most of its ready vesicles, and the calcium left over from each spike adds to the next, so release grows during the burst (facilitation); a slow, high-affinity calcium sensor, synaptotagmin-7, contributes to this at many synapses. A synapse with a high release probability spends its ready vesicles on the first spikes and cannot refill them fast enough, so release shrinks (depression). The same presynaptic train therefore reaches one target as a growing signal and another as a fading one. How do the SNARE proteins and synaptotagmin divide the job of fusing a vesicle? The SNAREs supply the force: synaptobrevin on the vesicle and syntaxin and SNAP-25 on the terminal wind into a four-helix bundle that zips toward the membranes and pulls them together. Before a spike they are held half-zipped, with the vesicle primed but not fused, by helper proteins such as complexin and Munc13. Synaptotagmin supplies the timing: when calcium binds its two C2 domains, they insert into the membrane and push the half-zipped complex over the last step, opening a fusion pore. Remove the SNAREs and nothing fuses; remove synaptotagmin-1 and fusion still happens, but slowly and out of step with the spike. Why does a small change in calcium entry change transmitter release so much? A vesicle fuses only when several calcium ions are bound to its sensor, synaptotagmin, so release grows roughly as release∝[Ca2+]4\text{release} \propto [\text{Ca}^{2+}]^{4}release∝[Ca2+]4, a relation first measured by Dodge and Rahamimoff in 1967. With that exponent, calcium entry cut by a fifth leaves 0.84≈0.410.8^{4} \approx 0.410.84≈0.41 of the release. The steepness makes calcium channels a powerful control point: presynaptic receptors for GABA, endocannabinoids or adenosine need only trim calcium entry slightly to silence a synapse. It also makes residual calcium from an earlier spike matter, which underlies facilitation.