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 language | English (US) |
|---|---|
| Pages (from-to) | 18664-18669 |
| Number of pages | 6 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 102 |
| Issue number | 51 |
| DOIs | |
| State | Published - Dec 20 2005 |
| Externally published | Yes |
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Keywords
- Ca sensor
- Exocytosis
- Gain-of-function
- Hippocampus
- Synaptic transmission
ASJC Scopus subject areas
- Genetics
- General
Cite this
Augmenting neurotransmitter release by enhancing the apparent Ca 2+ affinity of synaptotagmin 1. / Rhee, J. S.; Li, L. Y.; Shin, O. H.; Rah, J. C.; Rizo, J.; Südhof, T. C.; Rosenmund, C.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 102, No. 51, 20.12.2005, p. 18664-18669.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Augmenting neurotransmitter release by enhancing the apparent Ca 2+ affinity of synaptotagmin 1
AU - Rhee, J. S.
AU - Li, L. Y.
AU - Shin, O. H.
AU - Rah, J. C.
AU - Rizo, J.
AU - Südhof, T. C.
AU - Rosenmund, C.
PY - 2005/12/20
Y1 - 2005/12/20
N2 - 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.
AB - 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.
KW - Ca sensor
KW - Exocytosis
KW - Gain-of-function
KW - Hippocampus
KW - Synaptic transmission
UR - http://www.scopus.com/inward/record.url?scp=29444436513&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=29444436513&partnerID=8YFLogxK
U2 - 10.1073/pnas.0509153102
DO - 10.1073/pnas.0509153102
M3 - Article
C2 - 16352718
AN - SCOPUS:29444436513
VL - 102
SP - 18664
EP - 18669
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 51
ER -