Secretion of neuromodulatory peptides has often been proposed as a mechanism for regulating synaptic efficacy and for producing adaptive changes in behavior. At synapses, neuropeptides are released with other classical neurotransmitters and are thought to modulate the impact of the co-released neurotransmitters. Neuropeptides are packaged as proproteins into dense core vesicles or secretory granules, where they are enzymatically processed into biologically active peptides. To study the role of neuropeptides in modulating behavior, we have analyzed mutations in two neuropeptide processing enzymes. Proprotein convertases (PCs) cleave proneuropeptides at dibasic residues and carboxypeptidase E (CPE) removes the dibasic residues from the carboxy termini of the cleaved peptides. We previously reported that the
egl-3 gene encodes the worm homolog of PC2 (Kass and Kaplan IWM99) and that
egl-21 encodes the worm CPE (Carey and Kaplan WCWM00) . The genome sequence predicts three other PC genes and two additional carboxypeptidase genes; therefore, these mutants do not represent null mutations for neuropeptide biosynthesis. We have shown that the
egl-3 PC2 regulates the efficacy of sensory-interneuron synapses. Nose touch sensitivity (mediated by ASH sensory neurons) is defective in mutants lacking GLR-1 glutamate receptors (GluRs); however, mutations eliminating the
egl-3 PC2 restored nose touch sensitivity to
glr-1 GluR mutants. Mutants lacking the
egl-3 PC2 had increased sensitivity to nose touch whereas transgenic animals over-expressing the
egl-3 PC2 had decreased touch sensitivity. These results suggest that
egl-3 PC2 processed peptides regulate the gain of mechanosensory responses, perhaps by regulating the efficacy of ASH-interneuron synapses. We also show that
egl-3 PC2 and
egl-21 CPE both regulate synaptic efficacy at body wall neuromuscular junctions (NMJs). Both mutants are resistant to the paralytic effects of the acetylcholinesterase inhibitor aldicarb but are fully sensitive to the acetylcholine (ACh) agonist levamisole. These results suggest that
egl-3 PC2 and
egl-21 CPE mutants have decreased ACh release at NMJs. We will discuss candidate neuropeptides that may account for the effects of these mutations on touch sensitivity and locomotion.