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Submitted on July 20, 2006
Accepted on October 26, 2006
University of Texas Marine Science Institute, 750 Channel View Drive, Port Aransas, TX 78373, USA; Centre for Molecular and Biomolecular Informatics, Nijmegen Centre for Molecular Life Sciences, Radbout University Nijmegen, Toernooiveld 1, Nijmegen, 6500 GL, The Netherlands Department of Biology, East Carolina University, 1000 E. Fifth Street, NC 27858, USA
* To whom correspondence should be addressed. 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. Here 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 (GPCRs). 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), displaceable membrane binding specific for progestins. Progestins activate a pertussis toxin-sensitive inhibitory G protein (Gi) to down-regulate membrane-bound adenylyl cyclase activity in both st-mPR- and hu-mPR- transfected cells. Co-immunoprecipitation experiments demonstrate the receptors are directly coupled to the Gi protein. Similar to GPCRs, 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. PAQRs are related to the hemolysin3 (HLY3) 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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human •
seatrout •
G protein activation •
evolution steroid receptors
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