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Nonconserved Ca(2+)/calmodulin binding sites in Munc13s differentially control synaptic short-term plasticity.

Authors: Lipstein, N  Schaks, S  Dimova, K  Kalkhof, S  Ihling, C  Kolbel, K  Ashery, U  Rhee, J  Brose, N  Sinz, A  Jahn, O 
Citation: Lipstein N, etal., Mol Cell Biol. 2012 Nov;32(22):4628-41. doi: 10.1128/MCB.00933-12. Epub 2012 Sep 10.
Pubmed: (View Article at PubMed) PMID:22966208
DOI: Full-text: DOI:10.1128/MCB.00933-12

Munc13s are presynaptic proteins that mediate synaptic vesicle priming and thereby control the size of the readily releasable pool of vesicles. During high synaptic activity, Munc13-1 and its closely related homolog, ubMunc13-2, bind Ca(2+)/calmodulin, resulting in enhanced priming activity and in changes of short-term synaptic plasticity characteristics. Here, we studied whether bMunc13-2 and Munc13-3, two remote isoforms of Munc13-1 with a neuronal subtype-specific expression pattern, mediate synaptic vesicle priming and regulate short-term synaptic plasticity in a Ca(2+)/calmodulin-dependent manner. We identified a single functional Ca(2+)/calmodulin binding site in these isoforms and provide structural evidence that all Munc13s employ a common mode of interaction with calmodulin despite the lack of sequence homology between their Ca(2+)/calmodulin binding sites. Electrophysiological analysis showed that, during high-frequency activity, Ca(2+)/calmodulin binding positively regulates the priming activity of bMunc13-2 and Munc13-3, resulting in an increase in the size of the readily releasable pool of vesicles and subsequently in strong short-term synaptic enhancement of neurotransmission. We conclude that Ca(2+)/calmodulin-dependent regulation of priming activity is structurally and functionally conserved in all Munc13 proteins, and that the composition of Munc13 isoforms in a neuron differentially controls its short-term synaptic plasticity characteristics.


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CRRD Object Information
CRRD ID: 11535109
Created: 2016-09-21
Species: All species
Last Modified: 2016-09-21
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.