RRC ID 46229
著者 Wang X, Piccolo CW, Cohen BM, Buttner EA.
タイトル Transient receptor potential melastatin (TRPM) channels mediate clozapine-induced phenotypes in Caenorhabditis elegans.
ジャーナル J Neurogenet
Abstract The molecular mechanisms of action of antipsychotic drugs (APDs) are not fully understood. Here, we characterize phenotypes of missense and knockout mutations in the Caenorhabditis elegans transient receptor potential melastatin (TRPM) channel ortholog gtl-2, a candidate APD target identified in a genome-wide RNAi (RNA interference) screen for Suppressors of Clozapine-induced Larval Arrest (scla genes). We then employ the developmental phenotypes of gtl-2(lf) mutants to validate our previous gtl-2(RNAi) result. GTL-2 acts in the excretory canal cell to regulate Mg(2+) homeostasis. Using exc (excretory canal abnormal) gene mutants, we demonstrate that excretory canal cell function is necessary for clozapine-induced developmental delay and lethality. Moreover, cell-specific promoter-driven expression studies reveal that GTL-2 function in the excretory canal cell is important for its role in the SCLA phenotype. We then investigate the mechanism by which GTL-2 function in the excretory canal cell impacts clozapine-induced phenotypes. gtl-2(lf) mutations cause hypermagnesemia, and we show that exposure of the wild-type strain to high Mg(2+) phenocopies gtl-2(lf) with respect to suppression of clozapine-induced developmental delay and lethality. Our results suggest that GTL-2 TRPM channel function in the excretory canal cell is important for clozapine's developmental effects. TRP channels are expressed in mammalian brain and are implicated in the pathogenesis of mental illnesses but have not been previously implicated in APD action.
巻・号 28(1-2)
ページ 86-97
公開日 2014-1-1
DOI 10.3109/01677063.2013.879717
PMID 24564792
MeSH Animals Animals, Genetically Modified Antipsychotic Agents / pharmacology* Caenorhabditis elegans Caenorhabditis elegans Proteins / genetics* Caenorhabditis elegans Proteins / metabolism Clozapine / pharmacology* Dose-Response Relationship, Drug Eggs Gene Expression Regulation, Developmental / drug effects* Gene Expression Regulation, Developmental / genetics Larva / cytology Larva / drug effects Larva / growth & development Luminescent Proteins / genetics Luminescent Proteins / metabolism Magnesium / metabolism Magnesium Sulfate / pharmacology Mutation / genetics Neurons / drug effects Pharyngeal Muscles / drug effects Pharyngeal Muscles / physiology Phenotype* RNA Interference / physiology TRPM Cation Channels / deficiency TRPM Cation Channels / genetics*
IF 1.438
引用数 5
WOS 分野 GENETICS & HEREDITY NEUROSCIENCES
リソース情報
線虫 tm1463