6. Health-related Consequences of Female Reproductive Aging. The menopause represents the end of a woman's reproductive years and is associated with a precipitous decline in circulating gonadal hormones, including estrogen and progesterone. Since women have live well past the average age at which the menopause occurs, a substantial portion of a woman's life is spent in a hormone-deprived state. Also, many neuronal populations are normal targets of hormones such as progesterone, and thus, it is likely that the depletion of such hormones would greatly impact brain function and may contribute age-related brain dysfunction. While considerable emphasis has been placed on estrogen protective actions on brain function, the involvement and mechanisms for progesterone action have been less well studied, but whose impact on brain function may be no less significant than that implicated for estrogen. In this proposal, we postulate that the GABAA receptor is a central player in progesterone's neuroprotective actions. Classically, progesterone modulates GABAA receptor function through its 5alpha-reduced metabolite, allopregnanolone, which enhances GABA-gated chloride currents. However, our preliminary data show that progesterone, and not ?allopregnanolone, rapidly and reversibly inhibits GABA-gated currents. Further, we offer preliminary data to suggest that this effect of progesterone may involve the activation of signal transduction pathways. Recently, we identified that progesterone elicits the activation of such neuroprotection-related signal transduction pathways as the Mitogen-activated protein kinase (MAPK) pathway. Since the GABAA receptor is a phosphoprotein, and that phosphorylation of the GABAA receptor results in altered channel function, we propose that progesterone inhibits the GABAA receptor by phosphorylating discrete sites within the GABAA receptor complex, through the activation of the MAPK signaling pathway. Furthermore, we hypothesized that progesterone-induced inhibition of the GABAA receptor is consistent with progesterone's neuroprotective actions. These hypotheses will be tested using recombinant GABAA receptors expressed in HEK298 cells, where we will evaluate: 1) The importance of the MAPK pathway in mediating progesterone's effects on GABAA receptor function, 2) If phosphorylation of specific sites within GABAA receptor subunits are critical fro progesterone's actions, and 3) If such phosphorylation events are critical for progesterone cytoprotective actions.
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