A<i>C. elegans</i>genome-wide RNAi screen for altered levamisole sensitivity identifies genes required for muscle function

Abstract At the neuromuscular junction (NMJ), postsynaptic ionotropic acetylcholine receptors (AChRs) transduce a chemical signal released from cholinergic motor neuron into an electrical to induce muscle contraction. To identify regulators of function, we conducted genome-wide RNAi screen for genes required proper response levamisole, pharmacological agonist L-AChRs at Caenorhabditis elegans NMJ. A total 117 gene knockdowns were found cause levamisole hypersensitivity, while 18 resulted in resistance. Our identified conserved important function including some that are mutated congenital myasthenic syndrome, muscular dystrophy, myopathy, myotonic and mitochondrial myopathy. Of screen, further investigated those predicted play role endocytosis cell surface receptors. Loss Epsin homolog epn-1 caused hypersensitivity had opposing effects on levels GABAA receptors, resulting increased decreased abundance, respectively. We also examined other levamisole-hypersensitive phenotype when knocked down gas-1, which functions Complex I electron transport chain. Consistent with altered ATP synthesis impacting response, treatment wild-type animals L-AChR–dependent depletion levels. These results suggest paralytic ultimately lead metabolic exhaustion.