title: A genome-wide RNAi screen in Caenorhabditis elegans identifies the nicotinic acetylcholine receptor subunit ACR-7 as an antipsychotic drug target.
abstract: We report a genome-wide RNA interference (RNAi) screen for Suppressors of Clozapine-induced Larval Arrest (scla genes) in Caenorhabditis elegans, the first genetic suppressor screen for antipsychotic drug (APD) targets in an animal. The screen identifies 40 suppressors, including the α-like nicotinic acetylcholine receptor (nAChR) homolog acr-7. We validate the requirement for acr-7 by showing that acr-7 knockout suppresses clozapine-induced larval arrest and that expression of a full-length translational GFP fusion construct rescues this phenotype. nAChR agonists phenocopy the developmental effects of clozapine, while nAChR antagonists partially block these effects. ACR-7 is strongly expressed in the pharynx, and clozapine inhibits pharyngeal pumping. acr-7 knockout and nAChR antagonists suppress clozapine-induced inhibition of pharyngeal pumping. These findings suggest that clozapine activates ACR-7 channels in pharyngeal muscle, leading to tetanus of pharyngeal muscle with consequent larval arrest. No APDs are known to activate nAChRs, but a number of studies indicate that α7-nAChR agonists may prove effective for the treatment of psychosis. α-like nAChR signaling is a mechanism through which clozapine may produce its therapeutic and/or toxic effects in humans, a hypothesis that could be tested following identification of the mammalian ortholog of C. elegans acr-7.
authors.affiliation: Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Taixiang
authors.initials: T
authors.lastname: Saur
authors.forename: Sarah E
authors.initials: SE
authors.lastname: DeMarco
authors.forename: Angelica
authors.initials: A
authors.lastname: Ortiz
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Sliwoski
authors.forename: Limin
authors.initials: L
authors.lastname: Hao
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Cohen
authors.forename: Edgar A
authors.initials: EA
authors.lastname: Buttner
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000378:metabolism; D054316:Biomarkers, Pharmacological / Q000378:metabolism; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism; D003024:Clozapine / Q000494:pharmacology; D055786:Gene Knockout Techniques; D016678:Genome; D006801:Humans; D007814:Larva / Q000187:drug effects; D058990:Molecular Targeted Therapy; D018722:Nicotinic Agonists / Q000378:metabolism; D034622:RNA Interference; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D014150:Antipsychotic Agents; D054316:Biomarkers, Pharmacological; C579167:Chrna7 protein, human; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D003024:Clozapine