Transient receptor potential melastatin (TRPM) channels mediate clozapine-induced phenotypes in Caenorhabditis...

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.