title: Antipsychotics activate the TGFβ pathway effector SMAD3.
abstract: Although effective in treating an array of neurological disorders, antipsychotics are associated with deleterious metabolic side effects. Through high-throughput screening, we previously identified phenothiazine antipsychotics as modulators of the human insulin promoter. Here, we extended our initial finding to structurally diverse typical and atypical antipsychotics. We then identified the transforming growth factor beta (TGFβ) pathway as being involved in the effect of antipsychotics on the insulin promoter, finding that antipsychotics activated SMAD3, a downstream effector of the TGFβ pathway, through a receptor distinct from the TGFβ receptor family and known neurotransmitter receptor targets of antipsychotics. Of note, antipsychotics that do not cause metabolic side effects did not activate SMAD3. In vivo relevance was demonstrated by reanalysis of gene expression data from human brains treated with antipsychotics, which showed altered expression of SMAD3 responsive genes. This work raises the possibility that antipsychotics could be designed that retain beneficial CNS activity while lacking deleterious metabolic side effects.
authors.affiliation: Sanford Children's Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: T
authors.initials: T
authors.lastname: Cohen
authors.forename: S
authors.initials: S
authors.lastname: Sundaresh
authors.forename: F
authors.initials: F
authors.lastname: Levine
mesh_terms: D014150:Antipsychotic Agents / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D015870:Gene Expression / Q000187:drug effects; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D051900:Smad3 Protein / Q000819:agonists* / Q000502:physiology; D015534:Trans-Activators / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000502:physiology*
chemical_list: D014150:Antipsychotic Agents; D018398:Homeodomain Proteins; D051900:Smad3 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; C084010:pancreatic and duodenal homeobox 1 protein