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Department of Biology, East Carolina University, 1000 E. 5th Street, Greenville, North Carolina 27858-4553, USA
¹ Marine Science Institute, University of Texas at Austin, 750 Channelview Drive, Port Aransas, Texas 78373, USA

(Requests for offprints should be addressed to Y Zhu; Email: zhuy{at}mail.ecu.edu)

Recently, a unique family of membrane progestin receptors (mPR, mPRß, and mPR) was identified, which may be responsible for mediating rapid, nongenomic actions of progestins in a variety of target tissues. In this study, the mPR and mPRß isoforms from zebrafish were shown to be rapidly and specifically activated by the maturation-inducing steroid (MIS) of this species, 4-pregnen-17,20ß-diol-3-one (17,20ß-DHP). The zebrafish mPR and a previously uncharacterized mPRß isoform were stably expressed in nuclear progesterone receptor-deficient mammalian breast cancer cells, MDA-MB-231. Expression and surface localization of the receptors were verified by flow cytometry, biotin surface labeling, and Western blotting. Plasma membrane proteins from mPR- or mPRß-transfected cells showed high affinity (mPR, K_d 7 nM; mPRß, K_d 12 nM), saturable, displaceable, single-binding sites specific for 17,20ß-DHP, whereas negligible specific 17,20ß-DHP binding was observed in nontransfected cells. Progestin treatment caused significant activation of mitogen-activated protein kinase (MAPK) within 5 min in cells transfected with either of the receptors as measured by western blotting and flow cytometry. The rank order of the potencies of several progestins in activating MAPK via mPR and mPRß was the same (17,20ß-DHP>progesterone >4-pregnen-17,20ß,21-triol-3-one). Interestingly, the MIS in zebrafish, 17,20ß-DHP, was also the most potent inhibitor, among the progestins tested, of adenylyl cyclase activity in cells transfected with either of the receptors. This progestin significantly decreased cAMP levels in both mPR- and mPRß-transfected cells in a dose-responsive and time-dependent manner. In addition, signaling of the zebrafish mPR was blocked by pertussis toxin, implying activation of a G_i protein, while sensitivity to pertussis or cholera toxin was not shown with mPRß-mediated signaling, possibly indicating that this receptor activates a different pertussis toxin-insensitive G protein. The results of this study suggest that zebrafish mPR and mPRß signal similarly upon progestin binding resulting in rapid activation of MAPK and downregulation of adenylyl cyclase activity.

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