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Synaptotagmin 1 oligomers clamp and regulate different modes of neurotransmitter release.


ABSTRACT: Synaptotagmin 1 (Syt1) synchronizes neurotransmitter release to action potentials (APs) acting as the fast Ca2+ release sensor and as the inhibitor (clamp) of spontaneous and delayed asynchronous release. While the Syt1 Ca2+ activation mechanism has been well-characterized, how Syt1 clamps transmitter release remains enigmatic. Here we show that C2B domain-dependent oligomerization provides the molecular basis for the Syt1 clamping function. This follows from the investigation of a designed mutation (F349A), which selectively destabilizes Syt1 oligomerization. Using a combination of fluorescence imaging and electrophysiology in neocortical synapses, we show that Syt1F349A is more efficient than wild-type Syt1 (Syt1WT) in triggering synchronous transmitter release but fails to clamp spontaneous and synaptotagmin 7 (Syt7)-mediated asynchronous release components both in rescue (Syt1-/- knockout background) and dominant-interference (Syt1+/+ background) conditions. Thus, we conclude that Ca2+-sensitive Syt1 oligomers, acting as an exocytosis clamp, are critical for maintaining the balance among the different modes of neurotransmitter release.

SUBMITTER: Tagliatti E 

PROVIDER: S-EPMC7035618 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Synaptotagmin 1 oligomers clamp and regulate different modes of neurotransmitter release.

Tagliatti Erica E   Bello Oscar D OD   Mendonça Philipe R F PRF   Kotzadimitriou Dimitrios D   Nicholson Elizabeth E   Coleman Jeff J   Timofeeva Yulia Y   Rothman James E JE   Krishnakumar Shyam S SS   Volynski Kirill E KE  

Proceedings of the National Academy of Sciences of the United States of America 20200203 7


Synaptotagmin 1 (Syt1) synchronizes neurotransmitter release to action potentials (APs) acting as the fast Ca<sup>2+</sup> release sensor and as the inhibitor (clamp) of spontaneous and delayed asynchronous release. While the Syt1 Ca<sup>2+</sup> activation mechanism has been well-characterized, how Syt1 clamps transmitter release remains enigmatic. Here we show that C2B domain-dependent oligomerization provides the molecular basis for the Syt1 clamping function. This follows from the investigat  ...[more]

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