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Antipsychotics activate the TGFβ pathway effector SMAD3

Molecular Psychiatry volume 18, pages 347–357 (2013)Cite this article

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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.

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Acknowledgements

We thank Drs Joaquim Teixeira and Mark Mercola for the SMAD reporter constructs and for helpful discussion. Drs Susanne Heynen, Eduard Sergienko, and Fu-Yue Zeng at the SBMRI Conrad Prebys Center for Chemical Genomics provided the kinase inhibitor library and expertise in high-throughput screening. Drs Alexey Eroshkin and Xiayu Huang at the SBMRI Bioinformatics Core helped with processing gene expression data from GEO. Dr Tony Pinkerton was helpful in providing insights into structural aspects of the antipsychotics. Dr Elizabeth Thomas of the Scripps Research Institute provided access to additional data from her published microarray experiments. Funding: This work was funded by the Sanford Children's Health Research Center and the UCSD Biomedical Sciences Genetics Training Grant.

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  1. Sanford Children's Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA

    T Cohen & F Levine

  2. Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA, USA

    T Cohen

  3. NextBio, Cupertino, CA, USA

    S Sundaresh

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Correspondence to F Levine.

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Cohen, T., Sundaresh, S. & Levine, F. Antipsychotics activate the TGFβ pathway effector SMAD3. Mol Psychiatry 18, 347–357 (2013). https://doi.org/10.1038/mp.2011.186

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