Nonconserved Ca2+/calmodulin binding sites in Munc13s differentially control synaptic short-term plasticity

Noa Lipstein, Sabine Schaks, Kalina Dimova, Stefan Kalkhof, Christian Ihling, Knut Kölbel, Uri Ashery, Jeong Seop Rhee, Nils Brose, Andrea Sinz*, Olaf Jahn

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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 Ca2+/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 Ca2+/calmodulin-dependent manner. We identified a single functional Ca2+/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 Ca2+/calmodulin binding sites. Electrophysiological analysis showed that, during high-frequency activity, Ca2+/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 Ca2+/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.

Original languageEnglish
Pages (from-to)4628-4641
Number of pages14
JournalMolecular and Cellular Biology
Volume32
Issue number22
DOIs
StatePublished - Nov 2012

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