Journal of Molecular Histology

, Volume 41, Issue 2–3, pp 101–110 | Cite as

Broad tissue expression of membrane progesterone receptor Alpha in normal mice

Original Paper


The broad tissue distribution of membrane progesterone receptor alpha (mPRα) in vertebrates suggests multiple physiological functions of the receptor. Current knowledge regarding the receptor distribution, however, is largely obtained via non-histological assays. In this study, the tissue distribution of mPRα in mice of both sexes was described using both histological and non-histological methods. Immunohistochemical analysis revealed that abundant expression of mPRα was consistently detected in the cytoplasm and membrane of smooth muscles in vasculatures, gastro-intestines, and uterus. It was also observed in myoepithelial cells of mammary gland and intra-ovarian myofibroblasts. These findings suggest that mPRα may function as a mediator of P4 in regulating function of smooth muscles or smooth muscle-like cells in numerous physiological processes such as vasodilation, transportation of contents within luminary organs, relaxation of the uterine myometrium during pregnancy, release of oocytes, and milk secretion. In addition, strong mPRα expression was identified in the parietal cells of gastric glands, indicating the potential roles of P4/mPRα signaling in the modulation of gastric acid secretion. Surprisingly, in the testis of male mice mPRα was mainly seen in the nuclei, rather than cytoplasm and/or membrane, of the primary and secondary spermatocytes, suggesting a direct role of the receptor in gene regulation. Our results indicate that mPRα may function as a key modulator of P4 in the modulation of multiple physiological functions in normal mice.


Membrane progesterone receptor alpha Protein expression Tissue distribution 



We thank Mr. Max Green (Atlanta Research & Educational Foundation, Atlanta VA Medical Center) for his assistance in editing the manuscript. This work is supported by Department of Defense Breast Cancer Research Program Synergy Idea Award and Atlanta Research and Education Foundation Bridge Fund (S. You).


  1. Ashley RL, Clay CM, Farmerie TA, Niswender GD, Nett TM (2006) Cloning and characterization of an ovine intracellular seven transmembrane receptor for progesterone that mediates calcium mobilization. Endocrinology 147:4151–4159CrossRefPubMedGoogle Scholar
  2. Bouman A, Heineman MJ, Faas MM (2005) Sex hormones and the immune response in humans. Hum Reprod Update 11:411–423CrossRefPubMedGoogle Scholar
  3. Butts CL, Shukair SA, Duncan KM, Bowers E, Horn C, Belyavskaya E, Tonelli L, Sternberg EM (2007) Progesterone inhibits mature rat dendritic cells in a receptor-mediated fashion. Int Immunol 19:287–296CrossRefPubMedGoogle Scholar
  4. Cheng L, Pricolo V, Biancani P, Behar J (2008) Over expression of progesterone receptor B increases sensitivity of human colon muscle cells to progesterone. Am J Physiol Gastrointest Liver Physiol 295:G493–G502CrossRefPubMedGoogle Scholar
  5. Confavreux C, Hutchinson M, Hours MM, Cortinovis-Tourniaire P, Moreau T (1998) Rate of pregnancy-related relapse in multiple sclerosis. Pregnancy in Multiple Sclerosis Group. N Engl J Med 339:285–291CrossRefPubMedGoogle Scholar
  6. D’Eon T, Braun B (2002) The roles of estrogen and progesterone in regulating carbohydrate and fat utilization at rest and during exercise. J Womens Health Gend Based Med 11:225–237CrossRefPubMedGoogle Scholar
  7. Dosiou C, Hamilton AE, Pang Y, Overgaard MT, Tulac S, Dong J, Thomas P, Giudice LC (2008) Expression of membrane progesterone receptors on human T lymphocytes and Jurkat cells and activation of G-proteins by progesterone. J Endocrinol 196:67–77CrossRefPubMedGoogle Scholar
  8. Dressing GE, Thomas P (2007) Identification of membrane progestin receptors in human breast cancer cell lines and biopsies and their potential involvement in breast cancer. Steroids 72:111–116CrossRefPubMedGoogle Scholar
  9. Eliakim R, Abulafia O, Sherer DM (2000) Estrogen, progesterone and the gastrointestinal tract. J Reprod Med 45:781–788PubMedGoogle Scholar
  10. Falkenstein E, Meyer C, Eisen C, Scriba PC, Wehling M (1996) Full-length cDNA sequence of a progesterone membrane-binding protein from porcine vascular smooth muscle cells. Biochem Biophys Res Commun 229:86–89CrossRefPubMedGoogle Scholar
  11. Falkenstein E, Tillmann HC, Christ M, Feuring M, Wehling M (2000) Multiple actions of steroid hormones—a focus on rapid, nongenomic effects. Pharmacol Rev 52:513–556PubMedGoogle Scholar
  12. Fernandes MS, Pierron V, Michalovich D, Astle S, Thornton S, Peltoketo H, Lam EW, Gellersen B, Huhtaniemi I, Allen J et al (2005) Regulated expression of putative membrane progestin receptor homologues in human endometrium and gestational tissues. J Endocrinol 187:89–101CrossRefPubMedGoogle Scholar
  13. Fernandez-Capetillo O, Mahadevaiah SK, Celeste A, Romanienko PJ, Camerini-Otero RD, Bonner WM, Manova K, Burgoyne P, Nussenzweig A (2003) H2AX is required for chromatin remodeling and inactivation of sex chromosomes in male mouse meiosis. Dev Cell 4:497–508CrossRefPubMedGoogle Scholar
  14. Frye CA, Sumida K, Lydon JP, O’Malley BW, Pfaff DW (2006) Mid-aged and aged wild-type and progestin receptor knockout (PRKO) mice demonstrate rapid progesterone and 3alpha, 5alpha-THP-facilitated lordosis. Psychopharmacology (Berl) 185:423–432CrossRefGoogle Scholar
  15. Gellersen B, Fernandes MS, Brosens JJ (2009) Non-genomic progesterone actions in female reproduction. Hum Reprod Update 15:119–138CrossRefPubMedGoogle Scholar
  16. Gomez F, Ruiz P, Briceno F, Lopez R, Michan A (1998) Treatment with progesterone analogues decreases macrophage Fcgamma receptors expression. Clin Immunol Immunopathol 89:231–239CrossRefPubMedGoogle Scholar
  17. Graham JD, Clarke CL (1997) Physiological action of progesterone in target tissues. Endocr Rev 18:502–519CrossRefPubMedGoogle Scholar
  18. Hens JR, Wilson KM, Dann P, Chen X, Horowitz MC, Wysolmerski JJ (2005) TOPGAL mice show that the canonical Wnt signaling pathway is active during bone development and growth and is activated by mechanical loading in vitro. J Bone Miner Res 20:1103–1113CrossRefPubMedGoogle Scholar
  19. Kalo-Klein A, Witkin SS (1989) Candida albicans: cellular immune system interactions during different stages of the menstrual cycle. Am J Obstet Gynecol 161:1132–1136PubMedGoogle Scholar
  20. Kariagina A, Aupperlee MD, Haslam SZ (2007) Progesterone receptor isoforms and proliferation in the rat mammary gland during development. Endocrinology 148:2723–2736CrossRefPubMedGoogle Scholar
  21. Karteris E, Zervou S, Pang Y, Dong J, Hillhouse EW, Randeva HS, Thomas P (2006) Progesterone signaling in human myometrium through two novel membrane G protein-coupled receptors: potential role in functional progesterone withdrawal at term. Mol Endocrinol 20:1519–1534CrossRefPubMedGoogle Scholar
  22. Kastner P, Krust A, Turcotte B, Stropp U, Tora L, Gronemeyer H, Chambon P (1990) Two distinct estrogen-regulated promoters generate transcripts encoding the two functionally different human progesterone receptor forms A and B. EMBO J 9:1603–1614PubMedGoogle Scholar
  23. Kazeto Y, Goto-Kazeto R, Thomas P, Trant JM (2005) Molecular characterization of three forms of putative membrane-bound progestin receptors and their tissue-distribution in channel catfish, Ictalurus punctatus. J Mol Endocrinol 34:781–791CrossRefPubMedGoogle Scholar
  24. Kim S, Namekawa SH, Niswander LM, Ward JO, Lee JT, Bardwell VJ, Zarkower D (2007) A mammal-specific Doublesex homolog associates with male sex chromatin and is required for male meiosis. PLoS Genet 3:e62CrossRefPubMedGoogle Scholar
  25. Ko C, Gieske MC, Al-Alem L, Hahn Y, Su W, Gong MC, Iglarz M, Koo Y (2006) Endothelin-2 in ovarian follicle rupture. Endocrinology 147:1770–1779CrossRefPubMedGoogle Scholar
  26. Losel R, Wehling M (2003) Nongenomic actions of steroid hormones. Nat Rev Mol Cell Biol 4:46–56CrossRefPubMedGoogle Scholar
  27. Losel R, Breiter S, Seyfert M, Wehling M, Falkenstein E (2005) Classic and non-classic progesterone receptors are both expressed in human spermatozoa. Horm Metab Res 37:10–14CrossRefPubMedGoogle Scholar
  28. Mendelsohn ME, Karas RH (1999) The protective effects of estrogen on the cardiovascular system. N Engl J Med 340:1801–1811CrossRefPubMedGoogle Scholar
  29. Michaletz-Onody PA (1992) Peptic ulcer disease in pregnancy. Gastroenterol Clin North Am 21:817–826PubMedGoogle Scholar
  30. Minshall RD, Pavcnik D, Browne DL, Hermsmeyer K (2002) Nongenomic vasodilator action of progesterone on primate coronary arteries. J Appl Physiol 92:701–708PubMedGoogle Scholar
  31. Miyaura H, Iwata M (2002) Direct and indirect inhibition of Th1 development by progesterone and glucocorticoids. J Immunol 168:1087–1094PubMedGoogle Scholar
  32. Nelson JL, Ostensen M (1997) Pregnancy and rheumatoid arthritis. Rheum Dis Clin North Am 23:195–212CrossRefPubMedGoogle Scholar
  33. Oettel M, Mukhopadhyay AK (2004) Progesterone: the forgotten hormone in men? Aging Male 7:236–257CrossRefPubMedGoogle Scholar
  34. Pace MC, Thomas P (2005) Activation of a pertussis toxin-sensitive, inhibitory G-protein is necessary for steroid-mediated oocyte maturation in spotted seatrout. Dev Biol 285:70–79CrossRefPubMedGoogle Scholar
  35. Quinkler M, Bumke-Vogt C, Meyer B, Bahr V, Oelkers W, Diederich S (2003) The human kidney is a progesterone-metabolizing and androgen-producing organ. J Clin Endocrinol Metab 88:2803–2809CrossRefPubMedGoogle Scholar
  36. Richards JS (1980) Maturation of ovarian follicles: actions and interactions of pituitary and ovarian hormones on follicular cell differentiation. Physiol Rev 60:51–89PubMedGoogle Scholar
  37. Routley CE, Ashcroft GS (2009) Effect of estrogen and progesterone on macrophage activation during wound healing. Wound Repair Regen 17:42–50CrossRefPubMedGoogle Scholar
  38. Salomaa S, Pekki A, Sannisto T, Ylikomi T, Tuohimaa P (1989) Progesterone receptor is constitutively expressed in chicken intestinal mesothelium and smooth muscle. J Steroid Biochem 34:345–349CrossRefPubMedGoogle Scholar
  39. Schuffner AA, Bastiaan HS, Duran HE, Lin ZY, Morshedi M, Franken DR, Oehninger S (2002) Zona pellucida-induced acrosome reaction in human sperm: dependency on activation of pertussis toxin-sensitive G(i) protein and extracellular calcium, and priming effect of progesterone and follicular fluid. Mol Hum Reprod 8:722–727CrossRefPubMedGoogle Scholar
  40. Simoncini T, Genazzani AR (2000) Direct vascular effects of estrogens and selective estrogen receptor modulators. Curr Opin Obstet Gynecol 12:181–187CrossRefPubMedGoogle Scholar
  41. Smith R (2007) Parturition. N Engl J Med 356:271–283CrossRefPubMedGoogle Scholar
  42. Tesarik J, Moos J, Mendoza C (1993) Stimulation of protein tyrosine phosphorylation by a progesterone receptor on the cell surface of human sperm. Endocrinology 133:328–335CrossRefPubMedGoogle Scholar
  43. Thomas P (2004) Discovery of a new family of membrane progesterone receptors in vertebrates and detection of the alpha and beta subtypes in mouse brain, testis and uterus. Med Chem Res 13:202–209CrossRefGoogle Scholar
  44. Thomas P (2008) Characteristics of membrane progestin receptor alpha (mPRalpha) and progesterone membrane receptor component 1 (PGMRC1) and their roles in mediating rapid progestin actions. Front Neuroendocrinol 29:292–312CrossRefPubMedGoogle Scholar
  45. Thomas P, Tubbs C, Detweiler C, Das S, Ford L, Breckenridge-Miller D (2005) Binding characteristics, hormonal regulation and identity of the sperm membrane progestin receptor in Atlantic croaker. Steroids 70:427–433CrossRefPubMedGoogle Scholar
  46. Tokumoto M, Nagahama Y, Thomas P, Tokumoto T (2006) Cloning and identification of a membrane progestin receptor in goldfish ovaries and evidence it is an intermediary in oocyte meiotic maturation. Gen Comp Endocrinol 145:101–108CrossRefPubMedGoogle Scholar
  47. Tubbs C, Thomas P (2009) Progestin signaling through an olfactory G protein and membrane progestin receptor-alpha in Atlantic croaker sperm: potential role in induction of sperm hypermotility. Endocrinology 150:473–484CrossRefPubMedGoogle Scholar
  48. Wood PA, Bove K, You S, Chambers A, Hrushesky WJ (2005) Cancer growth and spread are saltatory and phase-locked to the reproductive cycle through mediators of angiogenesis. Mol Cancer Ther 4:1065–1075CrossRefPubMedGoogle Scholar
  49. You S, Li W, Kobayashi M, Xiong Y, Hrushesky W, Wood P (2004) Creation of a stable mammary tumor cell line that maintains fertility-cycle tumor biology of the parent tumor. In Vitro Cell Dev Biol Anim 40:187–195CrossRefPubMedGoogle Scholar
  50. Zhu Y, Bond J, Thomas P (2003a) Identification, classification, and partial characterization of genes in humans and other vertebrates homologous to a fish membrane progestin receptor. Proc Natl Acad Sci U S A 100:2237–2242CrossRefPubMedGoogle Scholar
  51. Zhu Y, Rice CD, Pang Y, Pace M, Thomas P (2003b) Cloning, expression, and characterization of a membrane progestin receptor and evidence it is an intermediary in meiotic maturation of fish oocytes. Proc Natl Acad Sci U S A 100:2231–2236CrossRefPubMedGoogle Scholar
  52. Zuo L, Li L, Wang Q, Fleming TP, You S (2009) Mammaglobin as a potential molecular target for breast cancer drug delivery. Cancer Cell Int 9:8CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  1. 1.Histo—pathology coreAtlanta Research and Educational Foundation (151F), Atlanta VA Medical CenterDecaturUSA
  2. 2.Department of PathologyAtlanta Research and Educational Foundation (151F), Atlanta VA Medical CenterDecaturUSA

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