The ovarian steroid hormones, estradiol and progesterone, regulate cellular functions in the central nervous system resulting in changes in physiology and reproductive behavior in a variety of species. Progesterone effects on sexual behavior are mediated not only through the """"""""classical"""""""" genomic mechanism of action involving the intracellular nuclear receptors, but also via rapid """"""""non-classical"""""""" pathways involving extra-nuclear signal transduction cascades. While the cellular and molecular mechanisms involved in the convergence of these two mechanisms are not well understood, it could involve """"""""cross-talk"""""""" between protein kinase-dependent signal transduction cascades initiated at the membrane and the nuclear transcription factors. Pronounced signal amplification achieved by the protein kinase cascades could alter phosphorylation dynamics within the neuronal cells to achieve additive, synergistic or redundant effects producing a multi-component, but coordinated molecular response, culminating in an unified behavioral outcome. This proposal focuses on the determination of the mechanisms of progesterone action that extend beyond the classical intracellular steroid receptor-mediated pathways. In particular, we propose to determine the biochemical and molecular events underlying the rapid progesterone-initiated signal transduction pathway(s).
Specific aim 1 will determine the mechanism underlying the rapid, progesterone-initiated signaling in areas associated with lordosis. We will test the hypothesis that the progesterone-initiated increases in cAMP activate mitogen activated protein kinase (MAPK) pathway in the hypothalamus and preoptic area (POA), the regions known to be associated with lordosis circuitry. We will determine whether activation of MAPK pathway results in the phosphorylation of downstream nuclear transcriptional targets like Ca+2/cAMP response element binding protein (CREB).
Specific aim 2 will determine the intracellular localization of the activated MAPK cascade by examining the distribution of p-MAPK and its down-stream effectors at the cellular level.
Specific aim 3 will test the hypothesis that the progesterone-activated MAPK-mediated cascade and its transcriptional targets mediate sexual behavior in vivo. Identification of such cross-talk signaling mechanisms will contribute to our understanding of the environmental and internal determinants of hormone-brain-behavior mechanisms.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH063954-04
Application #
6916258
Study Section
Special Emphasis Panel (ZRG1-IFCN-2 (01))
Program Officer
Winsky, Lois M
Project Start
2002-07-01
Project End
2007-04-30
Budget Start
2005-05-01
Budget End
2006-04-30
Support Year
4
Fiscal Year
2005
Total Cost
$313,625
Indirect Cost
Name
Baylor College of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Mani, Shaila K; Blaustein, Jeffrey D (2012) Neural progestin receptors and female sexual behavior. Neuroendocrinology 96:152-61
Mani, Shaila; Portillo, Wendy (2010) Activation of progestin receptors in female reproductive behavior: Interactions with neurotransmitters. Front Neuroendocrinol 31:157-71
Wu, T John; Pagano, E; Mani, S K (2009) A biological role for the gonadotrophin-releasing hormone (GnRH) metabolite, GnRH-(1-5). J Neuroendocrinol 21:293-8
Balasubramanian, B; Mani, S K (2009) Dopamine agonist signalling in the hypothalamus of female rats is independent of calcium-dependent kinases. J Neuroendocrinol 21:954-60
Mani, S K; Portillo, W; Reyna, A (2009) Steroid hormone action in the brain: cross-talk between signalling pathways. J Neuroendocrinol 21:243-7
Gill, John C; Wadas, Brandon; Chen, Peilin et al. (2008) The gonadotropin-releasing hormone (GnRH) neuronal population is normal in size and distribution in GnRH-deficient and GnRH receptor-mutant hypogonadal mice. Endocrinology 149:4596-604
Balasubramanian, Bhuvana; Portillo, Wendy; Reyna, Andrea et al. (2008) Nonclassical mechanisms of progesterone action in the brain: II. Role of calmodulin-dependent protein kinase II in progesterone-mediated signaling in the hypothalamus of female rats. Endocrinology 149:5518-26
Mani, Shaila (2008) Progestin receptor subtypes in the brain: the known and the unknown. Endocrinology 149:2750-6
Balasubramanian, Bhuvana; Portillo, Wendy; Reyna, Andrea et al. (2008) Nonclassical mechanisms of progesterone action in the brain: I. Protein kinase C activation in the hypothalamus of female rats. Endocrinology 149:5509-17
Roberts, James L; Mani, Shaila K; Woller, Michael J et al. (2007) LHRH-(1-5): a bioactive peptide regulating reproduction. Trends Endocrinol Metab 18:386-92

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