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ERK MAP kinase signaling in post-mortem brain of suicide subjects: differential regulation of upstream Raf kinases Raf-1 and B-Raf

Molecular Psychiatry volume 11, pages 86–98 (2006)Cite this article

Abstract

The Raf kinases Raf-1 and B-Raf are upstream activators of the extracellular signal-regulated kinase (ERK)-signaling pathway and therefore participates in many physiological functions in brain, including neuronal survival and synaptic plasticity. Previously, we observed that activation of ERK-1/2, the downstream component of ERK signaling, is significantly reduced in post-mortem brain of suicide victims. The present study was undertaken to further examine whether suicide brain is also associated with abnormalities in upstream molecules in ERK signaling. The study was performed in prefrontal cortex (PFC) and hippocampus obtained from 28 suicide victims and 21 normal controls. mRNA levels of Raf-1, B-Raf, and cyclophilin were measured by quantitative RT-PCR. Protein levels of Raf-1 and B-Raf were determined by Western blot, whereas their catalytic activities were determined by immunoprecipitation and enzymatic assays. It was observed that the catalytic activity of B-Raf was significantly reduced in PFC and hippocampus of suicide subjects. This decrease was associated with a decrease in its protein, but not mRNA, level. On the other hand, catalytic activity, and mRNA and protein levels, of Raf-1 were not altered in post-mortem brain of suicide subjects. The observed changes were not related to confounding variables; however, Raf-1 showed a negative correlation with age. Also, the changes in B-Raf were present in all suicide subjects, irrespective of psychiatric diagnosis. Our results of selective reduction in catalytic activity and expression of B-Raf but not Raf-1 suggest that B-Raf may be playing an important role in altered ERK signaling in brain of suicide subjects, and thus in the pathophysiology of suicide.

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Acknowledgements

This work was supported by NIMH R0168777, a Career Development Award (KO1MH 01836) from the NIMH, and a Young Investigator Award from the American Foundation for Suicide Prevention to Dr Y Dwivedi. We acknowledge with thanks the cooperation of John Smialek, MD, Chief Medical Examiner, and Dennis Chute, MD, Assistant Medical Examiner, in the collection of brain samples, Ms Terri U'Prichard for performing the psychological autopsies, and Boris Lapidus, MD, for the dissections.

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  1. Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, USA

    Y Dwivedi, H S Rizavi & G N Pandey

  2. Maryland Psychiatric Research Center, Baltimore, MD, USA

    R R Conley

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Dwivedi, Y., Rizavi, H., Conley, R. et al. ERK MAP kinase signaling in post-mortem brain of suicide subjects: differential regulation of upstream Raf kinases Raf-1 and B-Raf. Mol Psychiatry 11, 86–98 (2006). https://doi.org/10.1038/sj.mp.4001744

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