Journal Article

Augmenting Neurotransmitter Release by Enhancing the Apparent Ca2+ Affinity of Synaptotagmin 1

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

2005

Overview

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.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Animals / Biochemistry / Biological Sciences / Calcium - metabolism / Calcium - pharmacology / Cations, Divalent - metabolism / Cations, Divalent - pharmacology / Cells, Cultured / Glutamic Acid - metabolism / Lipids / Mice / Mice, Knockout / Models, Molecular / Mutation / Mutation - genetics / Neurology / Neurons / Neuroscience / Neurotransmitters / Phosphatidylinositols / Phospholipids / Protein Structure, Tertiary / Sensors / Synapses / Synaptotagmin I - chemistry / Synaptotagmin I - deficiency / Synaptotagmin I - genetics / Synaptotagmin I - metabolism / Synaptotagmins / Time Factors / Tryptophan - genetics / Tryptophan - metabolism