ROP, A DROSOPHILA HOMOLOG OF YEAST SEC1 AND VERTEBRATE N-SEC1 MUNC-18PROTEINS, IS A NEGATIVE REGULATOR OF NEUROTRANSMITTER RELEASE IN-VIVO

The mammalian homolog of the yeast Sec1p, n-Sec1/l Munc-18 has been de monstrated to bind the presynaptic membrane protein syntaxin, a putati ve synaptic vesicle docking protein. To determine the role of n-Sec1/M unc-18 in neurotransmitter release in vivo, we have overexpressed the Drosophila homolog, rep, in third instar larvae and measured the elect rophysiological consequences at the neuromuscular junction. A 3- to 5- fold induction of the rop protein causes a dramatic decrease in neurot ransmitter release, suggesting rop may restrict the ability of vesicle s to dock or of docked vesicles to fuse. Consistent with this hypothes is, rop overexpression also reduces the number of spontaneous vesicle fusions by more than 50%, and repetitive stimulation results in signif icant decreases in evoked responses similar to those observed in rab3a mutant mice. However, rop overexpression does not alter significantly the Ca2+ dependence of neurotransmitter release. We propose that the Drosophila n-Sec1/Munc-18 homolog plays a negative role in neurotransm itter release in vivo, in addition to its previously identified positi ve function, possibly by modulation of docking of synaptic vesicles or activation of a pre-fusion complex at the active zone.