Release of neurotransmitters at the synaptic junction is a primary mechanism of neuronal communication and is regulated by the synaptic vesicle (SV) cycle. Several components of the SV cycle were initially characterized in C. elegans. One of those, unc-13, is involved in normal presynaptic function. Mammalian homologues of unc-13 are Munc13-1, 13-2, and 13-3. These neuron-specific proteins lack N-terminal homology, but are highly conserved in their C-terminal regions. Here they contain a phorbal ester binding C1-domain and two C2-domains with homology to the PKC Ca2+/phospholipid-binding domain. The most abundant isoform, Munc 13-1, is a presynaptic receptor with high affinities for phorbol ester and DAG. In response to phorbol ester, Munc13-1 associates with the plasma membrane and acts as a stimulation dependent enhancer of neurotransmitter release. In addition, Munc13-1 interacts with components of the SV cycle (syntaxin, SNAP25, synaptobrevin, Doc2) and with a brain specific isoform of β-spectrin, a protein that interacts with the actin cytoskeleton. Thus, it is thought that Munc13 proteins function in signaling pathways that regulate the neuronal exocytic machinery.