Beta phorbol ester- and diacylglycerol-induced augmentation of transmitter release is mediated by Munc13s and not by PKCs.
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.
Rhee
Jeong Seop
JS
Abteilung Membranbiophysik, Max-Planck-Institut für Biophysikalische Chemie, Am Fassberg 11, D-37077 Göttingen, Bundesrepublik Deutschland.
Betz
Andrea
A
Pyott
Sonja
S
Reim
Kerstin
K
Varoqueaux
Frederique
F
Augustin
Iris
I
Hesse
Dörte
D
Südhof
Thomas C
TC
Takahashi
Masami
M
Rosenmund
Christian
C
Brose
Nils
N
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*
D004075:Diglycerides; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D010703:Phorbol Esters; C485549:Unc13b protein, mouse; D011493:Protein Kinase C