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Androgens activate mitogen‐activated protein kinase signaling: Role in neuroprotection
Author(s) -
Nguyen ThuyVi V.,
Yao Mingzhong,
Pike Christian J.
Publication year - 2005
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2005.03318.x
Subject(s) - mapk/erk pathway , neuroprotection , protein kinase a , kinase , microbiology and biotechnology , phosphorylation , androgen receptor , signal transduction , biology , androgen , ribosomal s6 kinase , dihydrotestosterone , endocrinology , neuroscience , protein kinase b , p70 s6 kinase 1 , hormone , genetics , prostate cancer , cancer
Recent evidence indicates that testosterone is neuroprotective, however, the underlying mechanism(s) remains to be elucidated. In this study, we investigated the hypothesis that androgens induce mitogen‐activated protein kinase (MAPK) signaling in neurons, which subsequently drives neuroprotection. We observed that testosterone and its non‐aromatizable metabolite dihydrotestosterone (DHT) rapidly and transiently activate MAPK in cultured hippocampal neurons, as evidenced by phosphorylation of extracellular signal‐regulated kinase (ERK)‐1 and ERK‐2. Importantly, pharmacological suppression of MAPK/ERK signaling blocked androgen‐mediated neuroprotection against β‐amyloid toxicity. Androgen activation of MAPK/ERK and neuroprotection also was observed in PC12 cells stably transfected with androgen receptor (AR), but in neither wild‐type nor empty vector‐transfected PC12 cells. Downstream of ERK phosphorylation, we observed that DHT sequentially increases p90 kDa ribosomal S6 kinase (Rsk) phosphorylation and phosphorylation‐dependent inactivation of Bcl‐2‐associated death protein (Bad). Prevention of androgen‐induced phosphorylation of Rsk and Bad blocked androgen neuroprotection. These findings demonstrate AR‐dependent androgen activation of MAPK/ERK signaling in neurons, and specifically identify a neuroprotective pathway involving downstream activation of Rsk and inactivation of Bad. Elucidation of androgen‐mediated neural signaling cascades will provide important insights into the mechanisms of androgen action in brain, and may present a framework for therapeutic intervention of age‐related neurodegenerative disorders.