Inhibition of Xenopus oocyte adenylate cyclase by progesterone: a novel mechanism of action.
Progesterone inhibits oocyte plasma membrane adenylate cyclase measured in the presence of GTP or Gpp(NH)p by a novel mechanism that involves a guanine nucleotide regulatory protein. A hormone receptor has been identified in the oocyte plasma membranes using the technique of photoaffinity labeling, and the amount of steroid covalently bound to the steroid receptor after photolysis correlates with the level of inhibition of adenylate cyclase activity and the EC50 for germinal vesicle breakdown. Inhibition of oocyte adenylate cyclase by both progesterone and 2', 5'-dideoxyadenosine, a potent P-site agonist, correlates with slowing of guanine nucleotide exchange. The steroid inhibition shares certain other common characteristics with P-site action, including inhibition of Gpp(NH)p-stimulated enzyme activity and a slowing of the rate of Gpp(NH)p activation of the enzyme that is inversely proportional to the concentration of guanine nucleotide. The steady-state velocity of the activated enzyme is also reduced by both hormones. However, a major difference between the actions of progesterone and the P-site agonist is in the effects of the divalent cation Mn2+. Whereas Mn2+ potentiates the inhibitory action of 2', 5'-DDA, the divalent cation abolishes the inhibitory action of progesterone, as would be predicted for receptor-mediated action. The lack of effect of IAP on progesterone inhibition of oocyte adenylate cyclase suggests that progesterone inhibition of oocyte adenylate cyclase is not mediated by the IAP substrate. Possible alternative models for the IAP-insensitive steroid inhibition of oocyte adenylate cyclase include a unique interaction with Ni that is not abolished by IAP or an action that involves Ns.
Sadler
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Maller
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D000241:Adenosine / Q000494:pharmacology; D000246:Adenosine Diphosphate Ribose / Q000378:metabolism; D037361:Adenylate Cyclase Toxin; D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D001427:Bacterial Toxins / Q000494:pharmacology; D001665:Binding Sites; D002462:Cell Membrane / Q000502:physiology; D002772:Cholera Toxin / Q000494:pharmacology; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006150:Guanine Nucleotides / Q000378:metabolism; D006165:Guanylyl Imidodiphosphate / Q000037:antagonists & inhibitors; D008540:Meiosis / Q000187:drug effects; D009865:Oocytes / Q000187:drug effects / Q000201:enzymology*; D011374:Progesterone / Q000494:pharmacology*; D011980:Receptors, Progesterone / Q000502:physiology; D010566:Virulence Factors, Bordetella; D014982:Xenopus laevis
D037361:Adenylate Cyclase Toxin; D000067956:Adenylyl Cyclase Inhibitors; D001427:Bacterial Toxins; D006150:Guanine Nucleotides; D011980:Receptors, Progesterone; D010566:Virulence Factors, Bordetella; D000246:Adenosine Diphosphate Ribose; D006165:Guanylyl Imidodiphosphate; D011374:Progesterone; D002772:Cholera Toxin; D019204:GTP-Binding Proteins; D000241:Adenosine