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PNAS 100 (5): 2231-2236

Copyright © 2003 by the National Academy of Sciences.

From the Cover


Cloning, expression, and characterization of a membrane progestin receptor and evidence it is an intermediary in meiotic maturation of fish oocytes

Yong Zhu*,{dagger}, Charles D. Rice{ddagger}, Yefei Pang*, Margaret Pace*, and Peter Thomas*,§

*Marine Science Institute, University of Texas at Austin, 750 Channel View Drive, Port Aransas, TX 78373; {dagger}Department of Biology, East Carolina University, 1000 East Fifth Street, Greenville, NC 27858; and {ddagger}Departments of Environmental Toxicology and Bioscience, Clemson University, 509 Westinghouse Road, Pendleton, SC 29670

Received for publication October 9, 2002.

Abstract: The structures of membrane receptors mediating rapid, nongenomic actions of steroids have not been identified. We describe the cloning of a cDNA from spotted seatrout ovaries encoding a protein that satisfies the following seven criteria for its designation as a steroid membrane receptor: plausible structure, tissue specificity, cellular distribution, steroid binding, signal transduction, hormonal regulation, and biological relevance. For plausible structure, computer modeling predicts that the protein has seven transmembrane domains, typical of G protein-coupled receptors. The mRNA (4.0 kb) is only detected in the brain and reproductive tissues on Northern blots. Antisera only detect the protein (40 kDa) in plasma membranes of reproductive tissues. The recombinant protein produced in an Escherichia coli expression system has a high affinity (Kd = 30 nM), saturable, displaceable, single binding site specific for progestins. Progestins alter signal transduction pathways, activating mitogen-activated protein kinase and inhibiting adenylyl cyclase, in a transfected mammalian cell line. Inhibition of adenylyl cyclase is pertussis toxin sensitive, suggesting the receptor may be coupled to an inhibitory G protein. Progestins and gonadotropin up-regulate both mRNA and protein levels in seatrout ovaries. Changes in receptor abundance in response to hormones and at various stages of oocyte development, its probable coupling to an inhibitory G protein and inhibition of progestin induction of oocyte maturation upon microinjection of antisense oligonucleotides are consistent with the identity of the receptor as an intermediary in oocyte maturation. These characteristics suggest the fish protein is a membrane progestin receptor mediating a "nonclassical" action of progestins to induce oocyte maturation in fish.

§ To whom correspondence should be addressed. E-mail: thomas{at}

Edited by Ronald W. Estabrook, University of Texas Southwestern Medical Center, Dallas, TX, and approved December 17, 2002

This paper was submitted directly (Track II) to the PNAS office.

Data deposition: The sequence reported in this paper has been deposited in the GenBank database (accession no. AF2062028).

See commentary on page 2168.

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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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I. M. Aparicio, M. Garcia-Herreros, L. C. O'Shea, C. Hensey, P. Lonergan, and T. Fair (2011)
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   Abstract »    Full Text »    PDF »
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J. Pharmacol. Exp. Ther. 337, 24-32
   Abstract »    Full Text »    PDF »
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W. Wu, S.-Q. Shi, H.-J. Huang, J. Balducci, and R. E. Garfield (2011)
Mol. Hum. Reprod. 17, 233-242
   Abstract »    Full Text »    PDF »
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S. Mesiano, Y. Wang, and E. R. Norwitz (2011)
Reproductive Sciences 18, 6-19
   Abstract »    Full Text »    PDF »
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M. Pi, A. L. Parrill, and L. D. Quarles (2010)
J. Biol. Chem. 285, 39953-39964
   Abstract »    Full Text »    PDF »
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C.-C. Chen, C.-S. Liang, A.-L. Kao, and C.-C. Yang (2010)
J. Exp. Bot. 61, 3305-3320
   Abstract »    Full Text »    PDF »
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X. D. Fu, L. Goglia, A. M. Sanchez, M. Flamini, M. S. Giretti, V. Tosi, A. R. Genazzani, and T. Simoncini (2010)
Endocr. Relat. Cancer 17, 431-443
   Abstract »    Full Text »    PDF »
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R. N. Hanna, S. C.J. Daly, Y. Pang, I. Anglade, O. Kah, P. Thomas, and Y. Zhu (2010)
Biol Reprod 82, 112-122
   Abstract »    Full Text »    PDF »
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M. A. Behera, Q. Dai, R. Garde, C. Saner, E. Jungheim, and T. M. Price (2009)
Am J Physiol Endocrinol Metab 297, E1089-E1096
   Abstract »    Full Text »    PDF »
Comparative endocrinology in the 21st century.
R. J. Denver, P. M. Hopkins, S. D. McCormick, C. R. Propper, L. Riddiford, S. A. Sower, and J. C. Wingfield (2009)
Integr. Comp. Biol. 49, 339-348
   Abstract »    Full Text »    PDF »
Mifepristone acts as progesterone antagonist of non-genomic responses but inhibits phytohemagglutinin-induced proliferation in human T cells.
C.H. Chien, J.N. Lai, C.F. Liao, O.Y. Wang, L.M. Lu, M.I. Huang, W.F. Lee, M.C. Shie, and E.J. Chien (2009)
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   Abstract »    Full Text »    PDF »
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S. Bunda, Y. Wang, T. F. Mitts, P. Liu, S. Arab, M. Arabkhari, and A. Hinek (2009)
J. Biol. Chem. 284, 16633-16647
   Abstract »    Full Text »    PDF »
Dominant Role of Nuclear Progesterone Receptor in the Control of Rat Periovulatory Granulosa Cell Apoptosis.
P. A. Friberg, D.G. J. Larsson, and H. Billig (2009)
Biol Reprod 80, 1160-1167
   Abstract »    Full Text »    PDF »
HHP1 is involved in osmotic stress sensitivity in Arabidopsis.
C.-c. Chen, C.-s. Liang, A.-l. Kao, and C.-c. Yang (2009)
J. Exp. Bot.
   Abstract »    Full Text »    PDF »
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J. Neurosci. 29, 1897-1903
   Abstract »    Full Text »    PDF »
Non-genomic progesterone actions in female reproduction.
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   Abstract »    Full Text »    PDF »
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E. R. Levin (2008)
Am J Physiol Regulatory Integrative Comp Physiol 295, R1425-R1430
   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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J. Biol. Chem. 283, 7109-7116
   Abstract »    Full Text »    PDF »
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F. Stormshak and C. V. Bishop (2008)
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   Abstract »    Full Text »    PDF »
Expression of membrane progesterone receptors on human T lymphocytes and Jurkat cells and activation of G-proteins by progesterone.
C Dosiou, A E Hamilton, Y Pang, M T Overgaard, S Tulac, J Dong, P Thomas, and L C Giudice (2008)
J. Endocrinol. 196, 67-77
   Abstract »    Full Text »    PDF »
Hormonal regulation of G{alpha}i2 and mPR{alpha} in immortalized human oviductal cell line OE-E6/E7.
K. S. Monkkonen, R. Aflatoonian, K.-F. Lee, W. S.B. Yeung, S.-W. Tsao, J. T. Laitinen, and A. Fazeli (2007)
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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A W Horne, E-N Lalani, R A Margara, and J O White (2006)
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   Abstract »    Full Text »    PDF »
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N. R. Chapman, M. M. Kennelly, K. A. Harper, G. N. Europe-Finner, and S. C. Robson (2006)
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   Abstract »    Full Text »    PDF »
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   Abstract »    PDF »
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J. Exp. Bot. 56, 3137-3147
   Abstract »    Full Text »    PDF »
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M. N. Chernova, D. H. Vandorpe, J. S. Clark, J. I. Williams, M. A. Zasloff, L. Jiang, and S. L. Alper (2005)
Am J Physiol Regulatory Integrative Comp Physiol 289, R1644-R1658
   Abstract »    Full Text »    PDF »
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M. C. Pace and P. Thomas (2005)
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   Abstract »    Full Text »    PDF »
Regulated expression of putative membrane progestin receptor homologues in human endometrium and gestational tissues.
M S Fernandes, V Pierron, D Michalovich, S Astle, S Thornton, H Peltoketo, E W-F Lam, B Gellersen, I Huhtaniemi, J Allen, et al. (2005)
J. Endocrinol. 187, 89-101
   Abstract »    Full Text »    PDF »
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Z. Zhang, A. M. Olland, Y. Zhu, J. Cohen, T. Berrodin, S. Chippari, C. Appavu, S. Li, J. Wilhem, R. Chopra, et al. (2005)
J. Biol. Chem. 280, 28468-28475
   Abstract »    Full Text »    PDF »
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J. G. Tasker, S. Di, and R. Malcher-Lopes (2005)
Integr. Comp. Biol. 45, 665-671
   Abstract »    Full Text »    PDF »
G-protein-coupled glucocorticoid receptors on the pituitary cell membrane.
C. Maier, D. Runzler, J. Schindelar, G. Grabner, W. Waldhausl, G. Kohler, and A. Luger (2005)
J. Cell Sci. 118, 3353-3361
   Abstract »    Full Text »    PDF »
Regulation of the G2/M Transition in Xenopus Oocytes by the cAMP-dependent Protein Kinase.
P. A. Eyers, J. Liu, N. R. Hayashi, A. L. Lewellyn, J. Gautier, and J. L. Maller (2005)
J. Biol. Chem. 280, 24339-24346
   Abstract »    Full Text »    PDF »
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D. P. Srivastava, E. J. Yu, K. Kennedy, H. Chatwin, V. Reale, M. Hamon, T. Smith, and P. D. Evans (2005)
J. Neurosci. 25, 6145-6155
   Abstract »    Full Text »    PDF »
Molecular characterization of three forms of putative membrane-bound progestin receptors and their tissue-distribution in channel catfish, Ictalurus punctatus.
Y. Kazeto, R. Goto-Kazeto, P. Thomas, and J. M Trant (2005)
J. Mol. Endocrinol. 34, 781-791
   Abstract »    Full Text »    PDF »
XGef Mediates Early CPEB Phosphorylation during Xenopus Oocyte Meiotic Maturation.
S. E. Martinez, L. Yuan, C. Lacza, H. Ransom, G. M. Mahon, I. P. Whitehead, and L. E. Hake (2005)
Mol. Biol. Cell 16, 1152-1164
   Abstract »    Full Text »    PDF »
Identification of a 71 kDa protein as a putative non-genomic membrane progesterone receptor in boar spermatozoa.
S Jang and L S H Yi (2005)
J. Endocrinol. 184, 417-425
   Abstract »    Full Text »    PDF »
Endocrine-like Signaling in Cnidarians: Current Understanding and Implications for Ecophysiology.
A. M. Tarrant (2005)
Integr. Comp. Biol. 45, 201-214
   Abstract »    Full Text »    PDF »
Potential role of protein tyrosine phosphatase nonreceptor type 13 in the control of oocyte meiotic maturation.
T. Nedachi and M. Conti (2004)
Development 131, 4987-4998
   Abstract »    Full Text »    PDF »
Changes in Androgen Receptor Nongenotropic Signaling Correlate with Transition of LNCaP Cells to Androgen Independence.
E. Unni, S. Sun, B. Nan, M. J. McPhaul, B. Cheskis, M. A. Mancini, and M. Marcelli (2004)
Cancer Res. 64, 7156-7168
   Abstract »    Full Text »    PDF »
Biochemical Characterization of a Membrane Androgen Receptor in the Ovary of the Atlantic Croaker (Micropogonias undulatus).
A. M. Braun and P. Thomas (2004)
Biol Reprod 71, 146-155
   Abstract »    Full Text »    PDF »
Aldosterone: Refreshing a Slow Hormone by Swift Action.
B. Boldyreff and M. Wehling (2004)
Physiology 19, 97-100
   Abstract »    Full Text »    PDF »
Ribozyme knockdown functionally links a 1,25(OH)2D3 membrane binding protein (1,25D3-MARRS) and phosphate uptake in intestinal cells.
I. Nemere, M. C. Farach-Carson, B. Rohe, T. M. Sterling, A. W. Norman, B. D. Boyan, and S. E. Safford (2004)
PNAS 101, 7392-7397
   Abstract »    Full Text »    PDF »
Myometrial Progesterone responsiveness and the Control of Human Parturition.
S. Mesiano (2004)
Reproductive Sciences 11, 193-202
   Abstract »    PDF »
Metalloregulation of yeast membrane steroid receptor homologs.
T. J. Lyons, N. Y. Villa, L. M. Regalla, B. R. Kupchak, A. Vagstad, and D. J. Eide (2004)
PNAS 101, 5506-5511
   Abstract »    Full Text »    PDF »
Diethylstilbestrol induces fish oocyte maturation.
T. Tokumoto, M. Tokumoto, R. Horiguchi, K. Ishikawa, and Y. Nagahama (2004)
PNAS 101, 3686-3690
   Abstract »    Full Text »    PDF »
Brain masculinization requires androgen receptor function.
T. Sato, T. Matsumoto, H. Kawano, T. Watanabe, Y. Uematsu, K. Sekine, T. Fukuda, K.-i. Aihara, A. Krust, T. Yamada, et al. (2004)
PNAS 101, 1673-1678
   Abstract »    Full Text »    PDF »
Nongenomic Inhibition of Oxytocin Binding by Progesterone in the Ovine Uterus.
K. A. Dunlap and F. Stormshak (2004)
Biol Reprod 70, 65-69
   Abstract »    Full Text »    PDF »
Proteins of Multiple Classes May Participate in Nongenomic Steroid Actions.
C. S. Watson and B. Gametchu (2003)
Experimental Biology and Medicine 228, 1272-1281
   Abstract »    Full Text »    PDF »
Rapid Signaling of Estrogen in Hypothalamic Neurons Involves a Novel G-Protein-Coupled Estrogen Receptor that Activates Protein Kinase C.
J. Qiu, M. A. Bosch, S. C. Tobias, D. K. Grandy, T. S. Scanlan, O. K. Ronnekleiv, and M. J. Kelly (2003)
J. Neurosci. 23, 9529-9540
   Abstract »    Full Text »    PDF »
Non-genomic actions of aldosterone: mechanisms and consequences in kidney cells.
B. Boldyreff and M. Wehling (2003)
Nephrol. Dial. Transplant. 18, 1693-1695
   Full Text »    PDF »
Signaling Receptome: A Genomic and Evolutionary Perspective of Plasma Membrane Receptors Involved in Signal Transduction.
I. Ben-Shlomo, S. Yu Hsu, R. Rauch, H. W. Kowalski, and A. J. W. Hsueh (2003)
Sci. STKE 2003, re9
   Abstract »    Full Text »    PDF »
SIGNAL TRANSDUCTION: Fishing at the Cell Surface.
J. L. Maller (2003)
Science 300, 594-595
   Abstract »    Full Text »    PDF »
The further redefining of steroid-mediated signaling.
S. R. Hammes (2003)
PNAS 100, 2168-2170
   Full Text »    PDF »
Identification, classification, and partial characterization of genes in humans and other vertebrates homologous to a fish membrane progestin receptor.
Y. Zhu, J. Bond, and P. Thomas (2003)
PNAS 100, 2237-2242
   Abstract »    Full Text »    PDF »

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