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Steroid and G Protein Binding Characteristics of the Seatrout and Human Progestin Membrane Receptor Subtypes and Their Evolutionary Origins

University of Texas Marine Science Institute (P.T., Y.P., J.D., C.T.), Port Aransas, Texas 78373; Centre for Molecular and Biomolecular Informatics (P.G., J.K., J.d.V.), Nijmegen Centre for Molecular Life Sciences, Radbout University Nijmegen, 6500 HC Nijmegen, The Netherlands; and Department of Biology (Y.Z.), East Carolina University, Greenville, North Carolina 27858

Address all correspondence and requests for reprints to: Peter Thomas, University of Texas Marine Science Institute, 750 Channel View Drive, Port Aransas, Texas 78373. E-mail: thomas{at}utmsi.utexas.edu.

A novel progestin receptor (mPR) with seven-transmembrane domains was recently discovered in spotted seatrout and homologous genes were identified in other vertebrates. We show that cDNAs for the mPR subtypes from spotted seatrout (st-mPR) and humans (hu-mPR) encode progestin receptors that display many functional characteristics of G protein-coupled receptors. Flow cytometry and immunocytochemical staining of whole MDA-MB-231 cells stably transfected with the mPRs using antibodies directed against their N-terminal regions show the receptors are localized on the plasma membrane and suggest the N-terminal domain is extracellular. Both recombinant st-mPR and hu-mPR display high affinity (Kd 4.2–7.8 nM), limited capacity (Bmax 0.03–0.32 nM), and displaceable membrane binding specific for progestins. Progestins activate a pertussis toxin-sensitive inhibitory G protein (G_i) to down-regulate membrane-bound adenylyl cyclase activity in both st-mPR- and hu-mPR-transfected cells. Coimmunoprecipitation experiments demonstrate the receptors are directly coupled to the G_i protein. Similar to G protein-coupled receptors, dissociation of the receptor/G protein complex results in a decrease in ligand binding to the mPRs and mutation of the C-terminal, and third intracellular loop of st-mPR causes loss of ligand-dependent G protein activation. Phylogenetic analysis indicates the mPRs are members of a progesterone and adipoQ receptor (PAQR) subfamily that is only present in chordates, whereas other PAQRs also occur in invertebrates and plants. Progesterone and adipoQ receptors are related to the hemolysin3 family and have origins in the Eubacteria. Thus, mPRs arose from Eubacteria independently from members of the GPCR superfamily, which arose from Archeabacteria, suggesting convergent evolution of seven-transmembrane hormone receptors coupled to G proteins.

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