title: Munc18-1 is a dynamically regulated PKC target during short-term enhancement of transmitter release.
abstract: Transmitter release at synapses is regulated by preceding neuronal activity, which can give rise to short-term enhancement of release like post-tetanic potentiation (PTP). Diacylglycerol (DAG) and Protein-kinase C (PKC) signaling in the nerve terminal have been widely implicated in the short-term modulation of transmitter release, but the target protein of PKC phosphorylation during short-term enhancement has remained unknown. Here, we use a gene-replacement strategy at the calyx of Held, a large CNS model synapse that expresses robust PTP, to study the molecular mechanisms of PTP. We find that two PKC phosphorylation sites of Munc18-1 are critically important for PTP, which identifies the presynaptic target protein for the action of PKC during PTP. Pharmacological experiments show that a phosphatase normally limits the duration of PTP, and that PTP is initiated by the action of a 'conventional' PKC isoform. Thus, a dynamic PKC phosphorylation/de-phosphorylation cycle of Munc18-1 drives short-term enhancement of transmitter release during PTP. DOI: http://dx.doi.org/10.7554/eLife.01715.001.
authors: Laboratory of Synaptic Mechanisms, Brain Mind Institute, School of Life Science, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors: Ozgür
authors: O
authors: Genc
authors: Olexiy
authors: O
authors: Kochubey
authors: Ruud F
authors: RF
authors: Toonen
authors: Matthijs
authors: M
authors: Verhage
authors: Ralf
authors: R
authors: Schneggenburger
mesh_terms: D000818:Animals; D051379:Mice; D051938:Munc18 Proteins / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*
chemical_list: D051938:Munc18 Proteins; D018377:Neurotransmitter Agents; C497938:Stxbp1 protein, mouse; D011493:Protein Kinase C
keywords: calyx of Held; protein kinase C; protein phosphatase; synaptic plasticity; synaptic transmission; transmitter release