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 |