Regulation of synaptic transmission is critical for proper nervous system function. Aberrant synaptic signaling is observed in many neurological and neurodegenerative diseases, ranging from epilepsy to Parkinson's Disease. The ubiquitin enzyme system controls the abundance of many synaptic proteins and thus plays a critical role in regulating synaptic transmission1,2. Misregulation of ubiquitin system function is also linked to neurological disorders. The Anaphase Promoting Complex (APC) is an ubiquitin ligase and a key regulator of protein turnover in the cell cycle3. Recent work in C. elegans, Drosophila, and mammals demonstrated novel roles for the APC in controlling synapse development and synaptic transmission through effects on pre- and postsynaptic protein abundance at glutamatergic synapses4-7. Much remains unknown, however, about how APC function is controlled in neurons and whether the APC may impact transmission at other synapse types. Here, we show that the APC regulates the balance of excitatory (acetylcholine) and inhibitory (GABA) signaling to control muscle contraction at a specialized synapse, the C. elegans neuromuscular junction (NMJ). Loss-of-function mutants in multiple APC subunits have increased excitatory transmission at the NMJ (
emb-30 APC4,
emb-27 CDC16,
mat-2 APC1, and
mat-3 CDC23), as indicated by their hypersensitivity to paralysis induced by the acetylcholine esterase inhibitor, aldicarb. Additional behavioral experiments, genetic analyses, and imaging studies support a presynaptic role for the APC in regulating signaling at this synapse. Rescue experiments in APC mutants, as well as assays testing responsiveness to a GABA antagonist, are consistent with a role for the APC in GABAergic neurons. Together, these data suggest a model in which the APC acts in GABAergic neurons to inhibit muscle contraction. Current studies are focused on confirming this site of action and testing whether the APC also functions in cholinergic neurons. Genetic and biochemical experiments to identify relevant APC substrates that mediate its effects at the NMJ are also ongoing. 1. Yi, J.J. and M.D. Ehlers. Pharmacological Reviews, 2007. 59:14-39. 2. Kowalski, J.R., et al, 2011. 31:1341-1354. 3. Peters, J.M. Mol Cell, 2002. 9:931-43. 4. Juo, P. and J.M. Kaplan. Curr Biol, 2004. 14:2057-62. 5. Yang, Y., et al. Science, 2009. 326:575-78. 6. van Roessel, P., et al. Cell, 2004. 119:707-18. 7. Fu, A.K.Y., et al., Nature Neuroscience, 2011. 14:181-9.