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A genome-wide RNAi screen in Caenorhabditis elegans identifies the nicotinic acetylcholine receptor subunit ACR-7 as an antipsychotic drug target.

Saur T, DeMarco SE, Ortiz A, Sliwoski GR, Hao L, Wang X, Cohen BM, Buttner EA - PLoS Genet. (2013)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, USA.

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.

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Functional diversity of scla genes.Genes were classified by biological process based on Gene Ontology terms from Wormbase. The percentages for each functional class of genes required for suppression of clozapine-induced larval arrest are shown.
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pgen-1003313-g002: Functional diversity of scla genes.Genes were classified by biological process based on Gene Ontology terms from Wormbase. The percentages for each functional class of genes required for suppression of clozapine-induced larval arrest are shown.

Mentions: The functional classes of the suppressors revealed that a more diverse group of genes was required for the biological effects of clozapine than had been previously appreciated. A fraction of these genes likely suppressed clozapine-induced larval arrest via indirect effects. However, molecules involved in signal transduction significantly outnumbered those in other functional classes, consistent with the idea that clozapine's developmental effects have a neuromuscular basis (Figure 2, [12], [19]). Moreover, the fraction of signal transduction genes from our RNAi screen was higher than that from a screen for all genes with RNAi phenotypes in C. elegans[27]. This difference indicated that our dataset was specific to the effects of clozapine.


A genome-wide RNAi screen in Caenorhabditis elegans identifies the nicotinic acetylcholine receptor subunit ACR-7 as an antipsychotic drug target.

Saur T, DeMarco SE, Ortiz A, Sliwoski GR, Hao L, Wang X, Cohen BM, Buttner EA - PLoS Genet. (2013)

Functional diversity of scla genes.Genes were classified by biological process based on Gene Ontology terms from Wormbase. The percentages for each functional class of genes required for suppression of clozapine-induced larval arrest are shown.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3585123&req=5

pgen-1003313-g002: Functional diversity of scla genes.Genes were classified by biological process based on Gene Ontology terms from Wormbase. The percentages for each functional class of genes required for suppression of clozapine-induced larval arrest are shown.
Mentions: The functional classes of the suppressors revealed that a more diverse group of genes was required for the biological effects of clozapine than had been previously appreciated. A fraction of these genes likely suppressed clozapine-induced larval arrest via indirect effects. However, molecules involved in signal transduction significantly outnumbered those in other functional classes, consistent with the idea that clozapine's developmental effects have a neuromuscular basis (Figure 2, [12], [19]). Moreover, the fraction of signal transduction genes from our RNAi screen was higher than that from a screen for all genes with RNAi phenotypes in C. elegans[27]. This difference indicated that our dataset was specific to the effects of clozapine.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, USA.

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.

Show MeSH
Related in: MedlinePlus