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Submitted on November 3, 2005
Accepted on January 4, 2006
Department of Pharmacology and Neuroscience and the Institute for Aging & Alzheimer's Disease Research, University of North Texas Health Science Center, Fort Worth, Texas
* To whom correspondence should be addressed. E-mail: msingh{at}hsc.unt.edu.
Androgens such as Dihydrotestosterone (DHT) are known to exert their effects through the activation of intracellular receptors that regulate the transcription of target genes. Alternatively, "non-genomic" mechanisms, including the activation of such signaling pathways as the mitogen-activated protein kinase (MAPK) pathways have been described. It is unclear, however, whether this latter mechanism of action is mediated by the classical androgen receptor (AR), or some alternative mechanism. Here, using a glial cell model (C6 cells) that we found to express the AR, we identified that DHT increased the phosphorylation of both ERK and Akt, key effectors of the neuroprotection-associated MAPK and phosphoinositide-3 kinase (PI-3K) signaling pathways, respectively, and ERK phosphorylation was blocked by the AR antagonist, flutamide. In contrast, the membrane-impermeable, BSA-conjugated androgen (DHT-BSA), caused a dose-dependent suppression of ERK and Akt phosphorylation, suggesting the existence of a novel membrane-associated AR that mediates this opposite effect on neuroprotective signaling. This is further supported by the observation of DHT-displaceable binding sites on the cell surface of live C6 cells. Collectively, these data support the existence of a novel membrane-associated AR in glial cells, and argue for the existence of two, potentially competing, pathways in a given cell or tissue. This mutual antagonism was supported by the ability of DHT-BSA to attenuate DHT-induced ERK phosphorylation. Thus, depending on the predominance of one receptor mechanism over another, the outcome of androgen treatment may be very different, and as such, could help explain existing discrepancies as to whether androgens are protective or damage-inducing.
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