Synaptotagmin 1 Oligomers Clamp and Regulate Different Modes of Neurotransmitter Release

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2020 Feb 5

PMID 32015138

Citations 33

Authors

Erica Tagliatti

Oscar D Bello

Philipe R F Mendonca

Dimitrios Kotzadimitriou

Elizabeth Nicholson

Jeff Coleman

Yulia Timofeeva

James E Rothman

Shyam S Krishnakumar

Kirill E Volynski

Affiliations

Soon will be listed here.

Abstract

Synaptotagmin 1 (Syt1) synchronizes neurotransmitter release to action potentials (APs) acting as the fast Ca release sensor and as the inhibitor (clamp) of spontaneous and delayed asynchronous release. While the Syt1 Ca 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 Syt1 is more efficient than wild-type Syt1 (Syt1) 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 Ca-sensitive Syt1 oligomers, acting as an exocytosis clamp, are critical for maintaining the balance among the different modes of neurotransmitter release.

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References

Bacaj T, Wu D, Burre J, Malenka R, Liu X, Sudhof T . Synaptotagmin-1 and -7 Are Redundantly Essential for Maintaining the Capacity of the Readily-Releasable Pool of Synaptic Vesicles. PLoS Biol. 2015; 13(10):e1002267. PMC: 4593569. DOI: 10.1371/journal.pbio.1002267. View

Brunger A, Choi U, Lai Y, Leitz J, Zhou Q . Molecular Mechanisms of Fast Neurotransmitter Release. Annu Rev Biophys. 2018; 47:469-497. PMC: 6378885. DOI: 10.1146/annurev-biophys-070816-034117. View

Littleton J, Stern M, Schulze K, Perin M, Bellen H . Mutational analysis of Drosophila synaptotagmin demonstrates its essential role in Ca(2+)-activated neurotransmitter release. Cell. 1993; 74(6):1125-34. DOI: 10.1016/0092-8674(93)90733-7. View

Rhee J, Li L, Shin O, Rah J, Rizo J, Sudhof T . Augmenting neurotransmitter release by enhancing the apparent Ca2+ affinity of synaptotagmin 1. Proc Natl Acad Sci U S A. 2005; 102(51):18664-9. PMC: 1311909. DOI: 10.1073/pnas.0509153102. View

Shin O, Xu J, Rizo J, Sudhof T . Differential but convergent functions of Ca2+ binding to synaptotagmin-1 C2 domains mediate neurotransmitter release. Proc Natl Acad Sci U S A. 2009; 106(38):16469-74. PMC: 2752550. DOI: 10.1073/pnas.0908798106. View

Ramirez D, Khvotchev M, Trauterman B, Kavalali E . Vti1a identifies a vesicle pool that preferentially recycles at rest and maintains spontaneous neurotransmission. Neuron. 2012; 73(1):121-34. PMC: 3259527. DOI: 10.1016/j.neuron.2011.10.034. View

Zhou Q, Zhou P, Wang A, Wu D, Zhao M, Sudhof T . The primed SNARE-complexin-synaptotagmin complex for neuronal exocytosis. Nature. 2017; 548(7668):420-425. PMC: 5757840. DOI: 10.1038/nature23484. View

Kaeser P, Regehr W . Molecular mechanisms for synchronous, asynchronous, and spontaneous neurotransmitter release. Annu Rev Physiol. 2013; 76:333-63. PMC: 4503208. DOI: 10.1146/annurev-physiol-021113-170338. View

Zanetti M, Bello O, Wang J, Coleman J, Cai Y, Sindelar C . Ring-like oligomers of Synaptotagmins and related C2 domain proteins. Elife. 2016; 5. PMC: 4977156. DOI: 10.7554/eLife.17262. View

10.

Ramakrishnan S, Bera M, Coleman J, Krishnakumar S, Pincet F, Rothman J . Synaptotagmin oligomers are necessary and can be sufficient to form a Ca -sensitive fusion clamp. FEBS Lett. 2018; 593(2):154-162. PMC: 6349546. DOI: 10.1002/1873-3468.13317. View

11.

Schneggenburger R, Rosenmund C . Molecular mechanisms governing Ca(2+) regulation of evoked and spontaneous release. Nat Neurosci. 2015; 18(7):935-41. DOI: 10.1038/nn.4044. View

12.

Bacaj T, Wu D, Yang X, Morishita W, Zhou P, Xu W . Synaptotagmin-1 and synaptotagmin-7 trigger synchronous and asynchronous phases of neurotransmitter release. Neuron. 2013; 80(4):947-59. PMC: 3888870. DOI: 10.1016/j.neuron.2013.10.026. View

13.

Zhou Q, Lai Y, Bacaj T, Zhao M, Lyubimov A, Uervirojnangkoorn M . Architecture of the synaptotagmin-SNARE machinery for neuronal exocytosis. Nature. 2015; 525(7567):62-7. PMC: 4607316. DOI: 10.1038/nature14975. View

14.

Pang Z, Cao P, Xu W, Sudhof T . Calmodulin controls synaptic strength via presynaptic activation of calmodulin kinase II. J Neurosci. 2010; 30(11):4132-42. PMC: 6632274. DOI: 10.1523/JNEUROSCI.3129-09.2010. View

15.

Geppert M, Goda Y, Hammer R, Li C, Rosahl T, Stevens C . Synaptotagmin I: a major Ca2+ sensor for transmitter release at a central synapse. Cell. 1994; 79(4):717-27. DOI: 10.1016/0092-8674(94)90556-8. View

16.

Paddock B, Wang Z, Biela L, Chen K, Getzy M, Striegel A . Membrane penetration by synaptotagmin is required for coupling calcium binding to vesicle fusion in vivo. J Neurosci. 2011; 31(6):2248-57. PMC: 3092483. DOI: 10.1523/JNEUROSCI.3153-09.2011. View

17.

Bello O, Jouannot O, Chaudhuri A, Stroeva E, Coleman J, Volynski K . Synaptotagmin oligomerization is essential for calcium control of regulated exocytosis. Proc Natl Acad Sci U S A. 2018; 115(32):E7624-E7631. PMC: 6094142. DOI: 10.1073/pnas.1808792115. View

18.

Li X, Radhakrishnan A, Grushin K, Kasula R, Chaudhuri A, Gomathinayagam S . Symmetrical organization of proteins under docked synaptic vesicles. FEBS Lett. 2018; 593(2):144-153. PMC: 6353562. DOI: 10.1002/1873-3468.13316. View

19.

Wang J, Li F, Bello O, Sindelar C, Pincet F, Krishnakumar S . Circular oligomerization is an intrinsic property of synaptotagmin. Elife. 2017; 6. PMC: 5576491. DOI: 10.7554/eLife.27441. View

20.

Sudhof T . Neurotransmitter release: the last millisecond in the life of a synaptic vesicle. Neuron. 2013; 80(3):675-90. PMC: 3866025. DOI: 10.1016/j.neuron.2013.10.022. View