dc.contributor.author | Saur, Taixiang | |
dc.contributor.author | DeMarco, Sarah E. | |
dc.contributor.author | Ortiz, Angelica | |
dc.contributor.author | Sliwoski, Gregory R. | |
dc.contributor.author | Hao, Limin | |
dc.contributor.author | Wang, Xin | |
dc.contributor.author | Cohen, Bruce Michael | |
dc.contributor.author | Buttner, Edgar (Ned) A. | |
dc.date.accessioned | 2013-05-08T14:26:51Z | |
dc.date.issued | 2013 | |
dc.identifier.citation | Saur, Taixiang, Sarah E. DeMarco, Angelica Ortiz, Gregory R. Sliwoski, Limin Hao, Xin Wang, Bruce M. Cohen, and Edgar A. Buttner. 2013. A genome-wide RNAi screen in Caenorhabditis elegans identifies the nicotinic acetylcholine receptor subunit ACR-7 as an antipsychotic drug target. PLoS Genetics 9(2): e1003313. | en_US |
dc.identifier.issn | 1553-7390 | en_US |
dc.identifier.uri | http://nrs.harvard.edu/urn-3:HUL.InstRepos:10612559 | |
dc.description.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. | en_US |
dc.language.iso | en_US | en_US |
dc.publisher | Public Library of Science | en_US |
dc.relation.isversionof | doi:10.1371/journal.pgen.1003313 | en_US |
dc.relation.hasversion | http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3585123/pdf/ | en_US |
dash.license | LAA | |
dc.title | A Genome-Wide RNAi Screen in Caenorhabditis elegans Identifies the Nicotinic Acetylcholine Receptor Subunit ACR-7 as an Antipsychotic Drug Target | en_US |
dc.type | Journal Article | en_US |
dc.description.version | Version of Record | en_US |
dc.relation.journal | PLoS Genetics | en_US |
dash.depositing.author | Cohen, Bruce Michael | |
dc.date.available | 2013-05-08T14:26:51Z | |
dc.identifier.doi | 10.1371/journal.pgen.1003313 | * |
dash.contributor.affiliated | Wang, Xin | |
dash.contributor.affiliated | Buttner, Edgar A. | |
dash.contributor.affiliated | Hao, Limin | |
dash.contributor.affiliated | Cohen, Bruce | |