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Human Homologs of the Putative G Protein-Coupled Membrane Progestin Receptors (mPR, ß, and ) Localize to the Endoplasmic Reticulum and Are Not Activated by Progesterone

Endokrinologikum Hamburg (T.K., M.H., B.G.), 20251 Hamburg, Germany; Institute of Reproductive and Developmental Biology (M.S.F., J.K., I.H., J.J.B.), and Cancer Research UK Labs, Department of Oncology (E.W.-F.L.), Imperial College London, Hammersmith Hospital, London W12 ONN, United Kingdom; and Department of Clinical Pharmacology (R.L.), School of Medicine Mannheim, University of Heidelberg, 68167 Mannheim, Germany

Address all correspondence and requests for reprints to: Birgit Gellersen, Ph.D., Endokrinologikum Hamburg, Falkenried 88, 20251 Hamburg, Germany. E-mail: gellersen{at}endokrinologikum.com; or Jan J. Brosens, M.D., Ph.D., Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Hospital, London W12 ONN, United Kingdom. E-mail: j.brosens{at}ic.ac.uk.

The steroid hormone progesterone exerts pleiotrophic functions in many cell types. Although progesterone controls transcriptional activation through binding to its nuclear receptors, it also initiates rapid nongenomic signaling events. Recently, three putative membrane progestin receptors (mPR, ß, and ) with structural similarity to G protein-coupled receptors have been identified. These mPR isoforms are expressed in a tissue-specific manner and belong to the larger, highly conserved family of progestin and adiponectin receptors found in plants, eubacteria, and eukaryotes. The fish mPR has been reported to mediate progesterone-dependent MAPK activation and inhibition of cAMP production through coupling to an inhibitory G protein. To functionally characterize the human homologs, we established human embryonic kidney 293 and MDA-MB-231 cell lines that stably express human mPR, ß, or . For comparison, we also established cell lines expressing the mPR cloned from the spotted seatrout (Cynoscion nebulosus) and Japanese pufferfish (Takifugu rubripes). Surprisingly, we found no evidence that human or fish mPRs regulate cAMP production or MAPK (ERK1/2 or p38) activation upon progesterone stimulation. Furthermore, the mPRs did not couple to a highly promiscuous G protein subunit, G_q5i, in transfection studies or provoke Ca²⁺ mobilization in response to progesterone. Finally, we demonstrate that transfected mPRs, as well as endogenous human mPR, localize to the endoplasmic reticulum, and that their expression does not lead to increased progestin binding either in membrane preparations or in intact cells. Our results therefore do not support the concept that mPRs are plasma membrane receptors involved in transducing nongenomic progesterone actions.

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Ligands:   Progesterone

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