| RRC ID |
46435
|
| 著者 |
Saur T, DeMarco SE, Ortiz A, Sliwoski GR, Hao L, Wang X, Cohen BM, Buttner EA.
|
| タイトル |
A genome-wide RNAi screen in Caenorhabditis elegans identifies the nicotinic acetylcholine receptor subunit ACR-7 as an antipsychotic drug target.
|
| ジャーナル |
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.
|
| 巻・号 |
9(2)
|
| ページ |
e1003313
|
| 公開日 |
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
|
| 引用数 |
20
|
|
WOS 分野
|
GENETICS & HEREDITY
|
| リソース情報 |
| 線虫 |
tm863
tm1463
tm4534
tm4806 |
