Androgens activate mitogen-activated protein kinase signaling: role in neuroprotection.
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 beta-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.
Nguyen
Thuy-Vi V
TV
Neuroscience Graduate Program, University of Southern California, Los Angeles, California 90089-0191, USA.
Yao
Mingzhong
M
Pike
Christian J
CJ
D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000633:toxicity; D000728:Androgens / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D019610:Cytoprotection / Q000187:drug effects / Q000502:physiology*; D013196:Dihydrotestosterone / Q000378:metabolism / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000378:metabolism* / Q000494:pharmacology; D016716:PC12 Cells; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011944:Receptors, Androgen / Q000235:genetics; D019893:Ribosomal Protein S6 Kinases; D013739:Testosterone / Q000378:metabolism / Q000494:pharmacology; D051025:bcl-Associated Death Protein
D016229:Amyloid beta-Peptides; D000728:Androgens; C494821:Bad protein, rat; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D011944:Receptors, Androgen; D051025:bcl-Associated Death Protein; D013196:Dihydrotestosterone; D013739:Testosterone; D011494:Protein Kinases; D019893:Ribosomal Protein S6 Kinases; D048049:Extracellular Signal-Regulated MAP Kinases