title: Nonconserved Ca(2+)/calmodulin binding sites in Munc13s differentially control synaptic short-term plasticity.
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 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.
authors.affiliation: Department of Molecular Neurobiology, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: Noa
authors.initials: N
authors.lastname: Lipstein
authors.forename: Sabine
authors.initials: S
authors.lastname: Schaks
authors.forename: Kalina
authors.initials: K
authors.lastname: Dimova
authors.forename: Stefan
authors.initials: S
authors.lastname: Kalkhof
authors.forename: Christian
authors.initials: C
authors.lastname: Ihling
authors.forename: Knut
authors.initials: K
authors.lastname: Kölbel
authors.forename: Uri
authors.initials: U
authors.lastname: Ashery
authors.forename: JeongSeop
authors.initials: J
authors.lastname: Rhee
authors.forename: Nils
authors.initials: N
authors.lastname: Brose
authors.forename: Andrea
authors.initials: A
authors.lastname: Sinz
authors.forename: Olaf
authors.initials: O
authors.lastname: Jahn
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism*; D002147:Calmodulin / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006624:Hippocampus / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000235:genetics*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010957:Plasmids; D061251:Primary Cell Culture; D011485:Protein Binding; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology; D014162:Transfection
chemical_list: D002147:Calmodulin; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; D011994:Recombinant Proteins; C485549:Unc13b protein, mouse; C485550:Unc13c protein, mouse; D002118:Calcium