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PMID: 16352718 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Augmenting neurotransmitter release by enhancing the apparent Ca2+ affinity of synaptotagmin 1.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 102 ·No. 51 ·2005-12-20 ·Pages 18664-9

Rhee JS, Li LY, Shin OH, Rah JC, Rizo J, Südhof TC, Rosenmund C

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 Ca2+ triggering of release.

MeSH Terms
Animals Calcium/metabolism,pharmacology Cations, Divalent/metabolism,pharmacology Cells, Cultured Glutamic Acid/metabolism Mice Mice, Knockout Models, Molecular Mutation/genetics Protein Structure, Tertiary Synaptotagmin I/chemistry,deficiency,genetics,metabolism Time Factors Tryptophan/genetics,metabolism
Chemicals
Cations, Divalent Synaptotagmin I Glutamic Acid Tryptophan Calcium
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Rhee J-S
Department of Neuroscience, Baylor College of Medicine, One Baylor Plaza, Houston, TX 7703, USA.
Li L Y
Shin O-H
Rah J-C
Rizo J
Südhof T C
Rosenmund C
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0509153102
Published
2005-12-20
Epub
2005-00-13
Pages
18664-9
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC1311909
Subset
IM
Grants
NINDS NIH HHS · R01 NS050655-05 · United States
NINDS NIH HHS · NS40944 · United States
NINDS NIH HHS · R01 NS040944 · United States
NINDS NIH HHS · NS50655 · United States
NINDS NIH HHS · R01 NS050655 · United States
External Links
PubMed source DOI: 10.1073/pnas.0509153102 PMC Full Text View journal details
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