Augmenting neurotransmitter release by enhancing the apparent Ca 2+ affinity of synaptotagmin 1

J. S. Rhee, L. Y. Li, O. H. Shin, J. C. Rah, J. Rizo, T. C. Südhof, C. Rosenmund

Research output: Contribution to journalArticle

101 Scopus citations

Abstract

Synaptotagmin 1 likely acts as a Ca2+ sensor in neurotransmitter release by Ca2+-binding to its two C2 domains. This notion was strongly supported by the observation that a mutation in the C2A domain causes parallel decreases in the apparent Ca2+ affinity of synaptotagmin 1 and in the Ca2+ sensitivity of release. However, this study was based on a single loss-of-function mutation. We now show that tryptophan substitutions in the synaptotagmin 1 C2 domains act as gain-of-function mutations to increase the apparent Ca2+ affinity of synaptotagmin 1. The same substitutions, when introduced into synaptotagmin 1 expressed in neurons, enhance the Ca2+ sensitivity of release. Mutations in the two C2 domains lead to comparable and additive effects in release. Our results thus show that the apparent Ca2+ sensitivity of release is dictated by the apparent Ca2+ affinity of synaptotagmin 1 in both directions, and that Ca2+ binding to both C2 domains contributes to Ca 2+ triggering of release.

Original languageEnglish (US)
Pages (from-to)18664-18669
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number51
DOIs
StatePublished - Dec 20 2005

Keywords

  • Ca sensor
  • Exocytosis
  • Gain-of-function
  • Hippocampus
  • Synaptic transmission

ASJC Scopus subject areas

  • General

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