Munc13 C 2 B domain is an activity-dependent Ca 2+ regulator of synaptic exocytosis

Ok Ho Shin, Jun Lu, Jeong Seop Rhee, Diana R. Tomchick, Zhiping P. Pang, Sonja M. Wojcik, Marcial Camacho-Perez, Nils Brose, Mischa MacHius, Josep Rizo, Christian Rosenmund, Thomas C. Südhof

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Abstract

Munc13 is a multidomain protein present in presynaptic active zones that mediates the priming and plasticity of synaptic vesicle exocytosis, but the mechanisms involved remain unclear. Here we use biophysical, biochemical and electrophysiological approaches to show that the central C 2 B domain of Munc13 functions as a Ca 2+ regulator of short-term synaptic plasticity. The crystal structure of the C 2 B domain revealed an unusual Ca 2+-binding site with an amphipathic α-helix. This configuration confers onto the C 2 B domain unique Ca 2+-dependent phospholipid-binding properties that favor phosphatidylinositolphosphates. A mutation that inactivated Ca 2+-dependent phospholipid binding to the C 2 B domain did not alter neurotransmitter release evoked by isolated action potentials, but it did depress release evoked by action-potential trains. In contrast, a mutation that increased Ca 2+-dependent phosphatidylinositolbisphosphate binding to the C 2 B domain enhanced release evoked by isolated action potentials and by action-potential trains. Our data suggest that, during repeated action potentials, Ca 2+ and phosphatidylinositolphosphate binding to the Munc13 C 2 B domain potentiate synaptic vesicle exocytosis, thereby offsetting synaptic depression induced by vesicle depletion.

Original languageEnglish (US)
Pages (from-to)280-288
Number of pages9
JournalNature Structural and Molecular Biology
Volume17
Issue number3
DOIs
StatePublished - Mar 1 2010

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ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

Cite this

Shin, O. H., Lu, J., Rhee, J. S., Tomchick, D. R., Pang, Z. P., Wojcik, S. M., Camacho-Perez, M., Brose, N., MacHius, M., Rizo, J., Rosenmund, C., & Südhof, T. C. (2010). Munc13 C 2 B domain is an activity-dependent Ca 2+ regulator of synaptic exocytosis. Nature Structural and Molecular Biology, 17(3), 280-288. https://doi.org/10.1038/nsmb.1758