Membrane Androgen Receptors in Neuroprotection

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DESCRIPTION (provided by applicant): Androgens influence much more than parameters related to reproductive function. Among the increasingly diverse functions regulated by androgens is their ability to influence cell survival, although the precise mechanism and receptor(s) that are involved remain unclear. Classically, the effects of androgens like dihydrotestosterone (DHT) are attributed to the regulation of gene transcription through the androgen receptor, a member of the nuclear steroid hormone receptor superfamily. However, recent evidence supports the ability of androgens to elicit "non-genomic" actions as well, including the ability to elicit signal transduction pathways. Here, we provide preliminary data that not only support the ability of androgens to influence cell signaling pathways relevant to promoting cell survival, but also offer evidence for a functional membrane-associated androgen receptor. Moreover, the consequences of activating the membrane- associated androgen receptor were different from activating the intracellular androgen receptor. We infer that cells or tissue that have relative differences in one receptor type over another may respond differently to androgens or their antagonists. As such, inconsistent findings as to whether androgens are protective or damaging may be due to the existence of two competing mechanisms, one via the intracellular receptor and the other via the classical intracellular receptor. Our hypothesis is that preferential activation of the membrane androgen receptor influences parameters related to cell protection differently than when intracellular receptors are activated. In this application, we will differentiate the consequences of activating the classical receptor versus the membrane-associated receptor in four complementary experimental systems that model neurons and glia. Specifically, we will determine whether neurons and glia have the same level of expression of the putative membrane androgen receptor. Secondly, we will assess how activation of this membrane androgen receptor influences 1) signal transduction relevant to neuroprotection, and 2) cell survival, in both the neuronal and glial models. The results obtained from the proposed experiments will provide new and important mechanistic details about the neurobiology of androgens that we believe will be pertinent to the development of novel androgen-based therapeutic strategies for such age- related diseases like Alzheimer's Disease.