title: Beta phorbol ester- and diacylglycerol-induced augmentation of transmitter release is mediated by Munc13s and not by PKCs.
abstract: Munc13-1 is a presynaptic protein with an essential role in synaptic vesicle priming. It contains a diacylglycerol (DAG)/beta phorbol ester binding C(1) domain and is a potential target of the DAG second messenger pathway that may act in parallel with PKCs. Using genetically modified mice that express a DAG/beta phorbol ester binding-deficient Munc13-1(H567K) variant instead of the wild-type protein, we determined the relative contribution of PKCs and Munc13-1 to DAG/beta phorbol ester-dependent regulation of neurotransmitter release. We show that Munc13s are the main presynaptic DAG/beta phorbol ester receptors in hippocampal neurons. Modulation of Munc13-1 activity by second messengers via the DAG/beta phorbol ester binding C(1) domain is essential for use-dependent alterations of synaptic efficacy and survival.
authors.affiliation: Abteilung Membranbiophysik, Max-Planck-Institut für Biophysikalische Chemie, Am Fassberg 11, D-37077 Göttingen, Bundesrepublik Deutschland.
authors.forename: Jeong Seop
authors.initials: JS
authors.lastname: Rhee
authors.forename: Andrea
authors.initials: A
authors.lastname: Betz
authors.forename: Sonja
authors.initials: S
authors.lastname: Pyott
authors.forename: Kerstin
authors.initials: K
authors.lastname: Reim
authors.forename: Frederique
authors.initials: F
authors.lastname: Varoqueaux
authors.forename: Iris
authors.initials: I
authors.lastname: Augustin
authors.forename: Dörte
authors.initials: D
authors.lastname: Hesse
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Südhof
authors.forename: Masami
authors.initials: M
authors.lastname: Takahashi
authors.forename: Christian
authors.initials: C
authors.lastname: Rosenmund
authors.forename: Nils
authors.initials: N
authors.lastname: Brose
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002478:Cells, Cultured; D004075:Diglycerides / Q000378:metabolism*; D015870:Gene Expression / Q000502:physiology; D006624:Hippocampus / Q000166:cytology; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008969:Molecular Sequence Data; D016296:Mutagenesis / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology; D010703:Phorbol Esters / Q000494:pharmacology*; D017354:Point Mutation / Q000502:physiology; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D013569:Synapses / Q000201:enzymology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
chemical_list: D004075:Diglycerides; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D010703:Phorbol Esters; C485549:Unc13b protein, mouse; D011493:Protein Kinase C