Reference - Detail
| RRC ID | 46435 |
|---|---|
| Author | Saur T, DeMarco SE, Ortiz A, Sliwoski GR, Hao L, Wang X, Cohen BM, Buttner EA. |
| Title | A genome-wide RNAi screen in Caenorhabditis elegans identifies the nicotinic acetylcholine receptor subunit ACR-7 as an antipsychotic drug target. |
| Journal | PLoS Genet |
| 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. |
| Volume | 9(2) |
| Pages | e1003313 |
| Published | 2013-1-1 |
| DOI | 10.1371/journal.pgen.1003313 |
| PII | PGENETICS-D-12-02006 |
| PMID | 23468647 |
| PMC | PMC3585123 |
| MeSH | Animals Antipsychotic Agents* / metabolism Biomarkers, Pharmacological / metabolism Caenorhabditis elegans* / genetics Caenorhabditis elegans* / metabolism Clozapine / pharmacology Gene Knockout Techniques Genome Humans Larva / drug effects Molecular Targeted Therapy Nicotinic Agonists / metabolism RNA Interference* Receptors, Nicotinic* / genetics Receptors, Nicotinic* / metabolism Signal Transduction / drug effects alpha7 Nicotinic Acetylcholine Receptor |
| IF | 5.175 |
| Times Cited | 20 |
| WOS Category | GENETICS & HEREDITY |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | Patent(IFI CLAIMS) |
| Total number of mentions | 2 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| C.elegans | tm863 tm1463 tm4534 tm4806 |