β 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)/β 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/β 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/β phorbol ester-dependent regulation of neurotransmitter release. We show that Munc13s are the main presynaptic DAG/β phorbol ester receptors in hippocampal neurons. Modulation of Munc13-1 activity by second messengers via the DAG/β phorbol ester binding C 1 domain is essential for use-dependent alterations of synaptic efficacy and survival.