Hormone action at the oocyte plasma membrane induces meiotic division and enables the oocyte to be fertilized, to expand the sperm nucleus, and to synthesize DNA. The maturation promoting factor which is synthesized in response to the meiotic stimulus may be a universal mitogen. Our recent work demonstrates that the earliest responses to progesterone induction (0-5 min) occur within the oocyte plasma membrane in Rana, and include a transient increase in phospholipid N-methylation, protease activation, Ca2+ release, protein kinase C activation, membrane phosphorylation, and, within 10 min, increased polyphosphoinositol turnover and increased membrane fluidity. We propose that the earliest response to progesterone may be the activation of methyltransferase I to produce phosphatidylmonomethylethanolamine (PME). PME in turn activates membrane protease(s) and limited proteolysis initiates the cascade of phospholipid changes associated with release of the prophase block. Our general aims include: 1) analysis of the composition and purity of the plasma membrane preparations used in the study, 2) determine whether PME synthesis in response to progesterone is the requisite step for activation of membrane protease and/or change the physical characteristics of the plasma membrane following progesterone treatment. 3) a more complete analysis of the protease activity changes following progesterone and/or PME treatment followed by a more specific plan to isolate and characterize the protease(s), and 4) to clearly establish the cause and effect relationships between protease activation, Ca2+ release, protein kinase activation, and oocyte activation. We will use biochemical methods involving protein and phospholipid isolation and purification and biophysical methods that include electrophysiological, nuclear magnetic resonance, and electron spin resonance techniques. This information will help explain the mechanism by which a membrane signal (progesterone) is transduced into metabolic changes that commit previously quiescent cells to undergo cell division and become responsive to a second mitogen (sperm). Knowledge in this area is essential to the understanding of problems related to fertility and to the control of cell growth, for example, the facilitation of tissue regeneration or the repression of cancer cells.

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Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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Reproductive Biology Study Section (REB)
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Albert Einstein College of Medicine
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Morrill, Gene A; Kostellow, Adele B; Gupta, Raj K (2015) Transmembrane helices in ""classical"" nuclear reproductive steroid receptors: a perspective. Nucl Recept Signal 13:e003
Morrill, Gene A; Kostellow, Adele B; Gupta, Raj K (2015) Computational analysis of the extracellular domain of the Ca²?-sensing receptor: an alternate model for the Ca²? sensing region. Biochem Biophys Res Commun 459:36-41
Morrill, Gene A; Kostellow, Adele B; Gupta, Raj K (2013) A computational analysis of non-genomic plasma membrane progestin binding proteins: signaling through ion channel-linked cell surface receptors. Steroids 78:1233-44
Morrill, Gene A; Kostellow, Adele B; Moore, Richard D et al. (2013) Plasma membrane events associated with the meiotic divisions in the amphibian oocyte: insights into the evolution of insulin transduction systems and cell signaling. BMC Dev Biol 13:3
Morrill, Gene A; Kostellow, Adele B; Askari, Amir (2012) Caveolin-Na/K-ATPase interactions: role of transmembrane topology in non-genomic steroid signal transduction. Steroids 77:1160-8
Morrill, Gene A; Dowd, Terry L; Kostellow, Adele B et al. (2011) Progesterone-induced changes in the phosphoryl potential during the meiotic divisions in amphibian oocytes: role of Na/K-ATPase. BMC Dev Biol 11:67
Morrill, Gene A; Kostellow, Adele B; Askari, Amir (2010) Progesterone modulation of transmembrane helix-helix interactions between the alpha-subunit of Na/K-ATPase and phospholipid N-methyltransferase in the oocyte plasma membrane. BMC Struct Biol 10:12
Morrill, Gene A; Kostellow, Adele B; Askari, Amir (2008) Progesterone binding to the alpha1-subunit of the Na/K-ATPase on the cell surface: insights from computational modeling. Steroids 73:27-40
Kostellow, Adele B; Morrill, Gene A (2008) Progesterone and subsequent polar metabolites are essential for completion of the first meiotic division in amphibian oocytes. Mol Cell Endocrinol 291:50-6
Morrill, Gene A; Schatz, Frederick; Kostellow, Adele et al. (2006) Gonadotropin stimulation of steroid synthesis and metabolism in the Rana pipiens ovarian follicle: sequential changes in endogenous steroids during ovulation, fertilization and cleavage stages. J Steroid Biochem Mol Biol 99:129-38

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