Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

Logo for

Mol. Biol. Cell 10 (10): 3113-3123

Copyright © 1999 by The American Society for Cell Biology.

Vol. 10, Issue 10, 3113-3123, October 1999

Testosterone Signaling through Internalizable Surface Receptors in Androgen Receptor-free Macrophages

W. Peter M. Benten,* Michèle Lieberherr,dagger Olaf Stamm,* Christian Wrehlke,* Zhiyong Guo,* and Frank Wunderlich*Dagger

 *Division of Molecular Parasitology and Centre of Biological-Medical Research, Heinrich-Heine-University, 40225 Duesseldorf, Germany; and  dagger Centre National de la Recherche Scientifique, Unité Propre de Recherche 1524, Institut National de la Recherche Agronomique, 78352 Jouy-en-Josas, France

Testosterone acts on cells through intracellular transcription-regulating androgen receptors (ARs). Here, we show that mouse IC-21 macrophages lack the classical AR yet exhibit specific nongenomic responses to testosterone. These manifest themselves as testosterone-induced rapid increase in intracellular free [Ca2+], which is due to release of Ca2+ from intracellular Ca2+ stores. This Ca2+ mobilization is also inducible by plasma membrane-impermeable testosterone-BSA. It is not affected by the AR blockers cyproterone and flutamide, whereas it is completely inhibited by the phospholipase C inhibitor U-73122 and pertussis toxin. Binding sites for testosterone are detectable on the surface of intact IC-21 cells, which become selectively internalized independent on caveolae and clathrin-coated vesicles upon agonist stimulation. Internalization is dependent on temperature, ATP, cytoskeletal elements, phospholipase C, and G-proteins. Collectively, our data provide evidence for the existence of G-protein-coupled, agonist-sequestrable receptors for testosterone in plasma membranes, which initiate a transcription-independent signaling pathway of testosterone.

Dagger    Corresponding author. E-mail address: frank.wunderlich{at}uni-duesseldorf.de.

Molecular Biology of the Cell
Vol. 10, 3113-3123, October 1999
Copyright © 1999 by The American Society for Cell Biology

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Disruption of Nongenomic Testosterone Signaling in a Model of Spinal and Bulbar Muscular Atrophy.
M. Schindler, C. Fabre, J. de Weille, S. Carreau, M. Mersel, and N. Bakalara (2012)
Mol. Endocrinol. 26, 1102-1116
   Abstract »    Full Text »    PDF »
Sex Differences and Sex Steroids in Lung Health and Disease.
E. A. Townsend, V. M. Miller, and Y. S. Prakash (2012)
Endocr. Rev. 33, 1-47
   Abstract »    Full Text »    PDF »
GPRC6A Mediates the Non-genomic Effects of Steroids.
M. Pi, A. L. Parrill, and L. D. Quarles (2010)
J. Biol. Chem. 285, 39953-39964
   Abstract »    Full Text »    PDF »
Non-classical actions of testosterone and spermatogenesis.
W. H. Walker (2010)
Phil Trans R Soc B 365, 1557-1569
   Abstract »    Full Text »    PDF »
Androgens Induce Nongenomic Stimulation of Colonic Contractile Activity through Induction of Calcium Sensitization and Phosphorylation of LC20 and CPI-17.
M. C. Gonzalez-Montelongo, R. Marin, T. Gomez, J. Marrero-Alonso, and M. Diaz (2010)
Mol. Endocrinol. 24, 1007-1023
   Abstract »    Full Text »    PDF »
Dihydrotestosterone alters cyclooxygenase-2 levels in human coronary artery smooth muscle cells.
K. L. Osterlund, R. J. Handa, and R. J. Gonzales (2010)
Am J Physiol Endocrinol Metab 298, E838-E845
   Abstract »    Full Text »    PDF »
Effects of methyltestosterone on immunity against Salmonella Pullorum in dwarf chicks.
H. Li, Y. Zhang, S. F. Zuo, Z. X. Lian, and N. Li (2009)
Poult. Sci. 88, 2539-2548
   Abstract »    Full Text »    PDF »
The Dark Side of Testosterone Deficiency: III. Cardiovascular Disease.
A. M. Traish, F. Saad, R. J. Feeley, and A. Guay (2009)
30, 477-494
   Abstract »    Full Text »    PDF »
A novel role of Shc adaptor proteins in steroid hormone-regulated cancers.
S. M. Alam, M. Rajendran, S. Ouyang, S. Veeramani, L. Zhang, and M.-F. Lin (2009)
Endocr. Relat. Cancer 16, 1-16
   Abstract »    Full Text »    PDF »
Androgens Transduce the G{alpha}s-Mediated Activation of Protein Kinase A in Prostate Cells.
G. Bagchi, J. Wu, J. French, J. Kim, N. H. Moniri, and Y. Daaka (2008)
Cancer Res. 68, 3225-3231
   Abstract »    Full Text »    PDF »
Evidence that Androgens Regulate Early Developmental Events, Prior to Sexual Differentiation.
D. R. Goldman-Johnson, D. M. de Kretser, and J. R. Morrison (2008)
Endocrinology 149, 5-14
   Abstract »    Full Text »    PDF »
Activation of a Membrane-Associated Androgen Receptor Promotes Cell Death in Primary Cortical Astrocytes.
J. W. Gatson and M. Singh (2007)
Endocrinology 148, 2458-2464
   Abstract »    Full Text »    PDF »
Testosterone Activates Mitogen-Activated Protein Kinase via Src Kinase and the Epidermal Growth Factor Receptor in Sertoli Cells.
J. Cheng, S. C. Watkins, and W. H. Walker (2007)
Endocrinology 148, 2066-2074
   Abstract »    Full Text »    PDF »
Matriptase activation and shedding with HAI-1 is induced by steroid sex hormones in human prostate cancer cells, but not in breast cancer cells.
K.-i. Kiyomiya, M.-S. Lee, I-C. Tseng, H. Zuo, R. J. Barndt, M. D. Johnson, R. B. Dickson, and C.-Y. Lin (2006)
Am J Physiol Cell Physiol 291, C40-C49
   Abstract »    Full Text »    PDF »
Selective Inhibition of L-Type Ca2+ Channels in A7r5 Cells by Physiological Levels of Testosterone.
J. Hall, R. D. Jones, T. H. Jones, K. S. Channer, and C. Peers (2006)
Endocrinology 147, 2675-2680
   Abstract »    Full Text »    PDF »
Activation of membrane androgen receptors potentiates the antiproliferative effects of paclitaxel on human prostate cancer cells.
M. Kampa, C. Kogia, P. A. Theodoropoulos, P. Anezinis, I. Charalampopoulos, E. A. Papakonstanti, E. N. Stathopoulos, A. Hatzoglou, C. Stournaras, A. Gravanis, et al. (2006)
Mol. Cancer Ther. 5, 1342-1351
   Abstract »    Full Text »    PDF »
Dihydrotestosterone Differentially Modulates the Mitogen-Activated Protein Kinase and the Phosphoinositide 3-Kinase/Akt Pathways through the Nuclear and Novel Membrane Androgen Receptor in C6 Cells.
J. W. Gatson, P. Kaur, and M. Singh (2006)
Endocrinology 147, 2028-2034
   Abstract »    Full Text »    PDF »
Testosterone Induces an Intracellular Calcium Increase by a Nongenomic Mechanism in Cultured Rat Cardiac Myocytes.
J. M. Vicencio, C. Ibarra, M. Estrada, M. Chiong, D. Soto, V. Parra, G. Diaz-Araya, E. Jaimovich, and S. Lavandero (2006)
Endocrinology 147, 1386-1395
   Abstract »    Full Text »    PDF »
Ca2+ oscillations induced by testosterone enhance neurite outgrowth.
M. Estrada, P. Uhlen, and B. E. Ehrlich (2006)
J. Cell Sci. 119, 733-743
   Abstract »    Full Text »    PDF »
Castration reduces platelet thromboxane A2 receptor density and aggregability.
A.A.L. Ajayi and P.V. Halushka (2005)
QJM 98, 349-356
   Abstract »    Full Text »    PDF »
Capacitative calcium entry in testosterone-induced intracellular calcium oscillations in myotubes.
M Estrada, A Espinosa, C J Gibson, P Uhlen, and E Jaimovich (2005)
J. Endocrinol. 184, 371-379
   Abstract »    Full Text »    PDF »
Testosterone Suppresses Protective Responses of the Liver to Blood-Stage Malaria.
J. Krucken, M. A. Dkhil, J. V. Braun, R. M. U. Schroetel, M. El-Khadragy, P. Carmeliet, H. Mossmann, and F. Wunderlich (2005)
Infect. Immun. 73, 436-443
   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 »
Estrogen receptor-{alpha} deficiency promotes increased TNF-{alpha} secretion and bacterial killing by murine macrophages in response to microbial stimuli in vitro.
K. C. Lambert, E. M. Curran, B. M. Judy, D. B. Lubahn, and D. M. Estes (2004)
J. Leukoc. Biol. 75, 1166-1172
   Abstract »    Full Text »    PDF »
Testosterone as a Modulator of Vascular Behavior.
M. Littleton-Kearney and P. D. Hurn (2004)
Biol Res Nurs 5, 276-285
   Abstract »    PDF »
Signaling Cross-talk from G{beta}4 Subunit to Elk-1 in the Rapid Action of Androgens.
Y. Zagar, G. Chaumaz, and M. Lieberherr (2004)
J. Biol. Chem. 279, 2403-2413
   Abstract »    Full Text »    PDF »
Androgens Inhibit Estradiol-17{beta} Synthesis in Atlantic Croaker (Micropogonias undulatus) Ovaries by a Nongenomic Mechanism Initiated at the Cell Surface.
A. M. Braun and P. Thomas (2003)
Biol Reprod 69, 1642-1650
   Abstract »    Full Text »    PDF »
Testosterone Stimulates Intracellular Calcium Release and Mitogen-Activated Protein Kinases Via a G Protein-Coupled Receptor in Skeletal Muscle Cells.
M. Estrada, A. Espinosa, M. Muller, and E. Jaimovich (2003)
Endocrinology 144, 3586-3597
   Abstract »    Full Text »    PDF »
Shape bistability of a membrane neck: A toggle switch to control vesicle content release.
V. A. Frolov, V. A. Lizunov, A. Y. Dunina-Barkovskaya, A. V. Samsonov, and J. Zimmerberg (2003)
PNAS 100, 8698-8703
   Abstract »    Full Text »    PDF »
Nongenomic Steroid Action: Controversies, Questions, and Answers.
R. M. LOSEL, E. FALKENSTEIN, M. FEURING, A. SCHULTZ, H.-C. TILLMANN, K. ROSSOL-HASEROTH, and M. WEHLING (2003)
Physiol Rev 83, 965-1016
   Abstract »    Full Text »    PDF »
Archvillin, a muscle-specific isoform of supervillin, is an early expressed component of the costameric membrane skeleton.
S. W. Oh, R. K. Pope, K. P. Smith, J. L. Crowley, T. Nebl, J. B. Lawrence, and E. J. Luna (2003)
J. Cell Sci. 116, 2261-2275
   Abstract »    Full Text »    PDF »
A Rapid, Nongenomic, Signaling Pathway Regulates the Actin Reorganization Induced by Activation of Membrane Testosterone Receptors.
E. A. Papakonstanti, M. Kampa, E. Castanas, and C. Stournaras (2003)
Mol. Endocrinol. 17, 870-881
   Abstract »    Full Text »    PDF »
Cloning, expression, and characterization of a membrane progestin receptor and evidence it is an intermediary in meiotic maturation of fish oocytes.
Y. Zhu, C. D. Rice, Y. Pang, M. Pace, and P. Thomas (2003)
PNAS 100, 2231-2236
   Abstract »    Full Text »    PDF »
Differential Regulation of Gonadotropin-Releasing Hormone Secretion and Gene Expression by Androgen: Membrane Versus Nuclear Receptor Activation.
T. Shakil, A. N. E. Hoque, M. Husain, and D. D. Belsham (2002)
Mol. Endocrinol. 16, 2592-2602
   Abstract »    Full Text »    PDF »
Testosterone Regulates 25-Hydroxycholesterol Production in Testicular Macrophages.
Y. Lukyanenko, J.-J. Chen, and J. C. Hutson (2002)
Biol Reprod 67, 1435-1438
   Abstract »    Full Text »    PDF »
Estrogen Modulation of Endothelial Nitric Oxide Synthase.
K. L. Chambliss and P. W. Shaul (2002)
Endocr. Rev. 23, 665-686
   Abstract »    Full Text »    PDF »
The Roles of Androgen Receptors and Androgen-Binding Proteins in Nongenomic Androgen Actions.
C. A. Heinlein and C. Chang (2002)
Mol. Endocrinol. 16, 2181-2187
   Abstract »    Full Text »    PDF »
Nongenomic Testosterone Calcium Signaling. GENOTROPIC ACTIONS IN ANDROGEN RECEPTOR-FREE MACROPHAGES.
Z. Guo, W. P. M. Benten, J. Krucken, and F. Wunderlich (2002)
J. Biol. Chem. 277, 29600-29607
   Abstract »    Full Text »    PDF »
Rapid Actions of Steroid Receptors in Cellular Signaling Pathways.
A. C. B. Cato, A. Nestl, and S. Mink (2002)
Sci. STKE 2002, re9
   Abstract »    Full Text »    PDF »
Estrogen Action Via the G Protein-Coupled Receptor, GPR30: Stimulation of Adenylyl Cyclase and cAMP-Mediated Attenuation of the Epidermal Growth Factor Receptor-to-MAPK Signaling Axis.
E. J. Filardo, J. A. Quinn, A. R. Frackelton Jr., and K. I. Bland (2002)
Mol. Endocrinol. 16, 70-84
   Abstract »    Full Text »    PDF »
Are Estrogens of Import to Primate/Human Ovarian Folliculogenesis?.
S. F. Palter, A. B. Tavares, A. Hourvitz, J. D. Veldhuis, and E. Y. Adashi (2001)
Endocr. Rev. 22, 389-424
   Abstract »    Full Text »    PDF »
Estradiol Signaling via Sequestrable Surface Receptors.
W. P. M. Benten, C. Stephan, M. Lieberherr, and F. Wunderlich (2001)
Endocrinology 142, 1669-1677
   Abstract »    Full Text »
Alterations in Development, Behavior, and Physiology in Drosophila Larva That Have Reduced Ecdysone Production.
H. Li, D. Harrison, G. Jones, D. Jones, and R. L. Cooper (2001)
J Neurophysiol 85, 98-104
   Abstract »    Full Text »    PDF »
Multiple Actions of Steroid Hormones--A Focus on Rapid, Nongenomic Effects.
E. Falkenstein, H.-C. Tillmann, M. Christ, M. Feuring, and M. Wehling (2000)
Pharmacol. Rev. 52, 513-556
   Abstract »    Full Text »    PDF »
Nongenomic actions of estrogens and xenoestrogens by binding at a plasma membrane receptor unrelated to estrogen receptor alpha and estrogen receptor beta.
A. Nadal, A. B. Ropero, O. Laribi, M. Maillet, E. Fuentes, and B. Soria (2000)
PNAS 97, 11603-11608
   Abstract »    Full Text »    PDF »
Estrogen-Induced Activation of Erk-1 and Erk-2 Requires the G Protein-Coupled Receptor Homolog, GPR30, and Occurs via Trans-Activation of the Epidermal Growth Factor Receptor through Release of HB-EGF.
E. J. Filardo, J. A. Quinn, K. I. Bland, and A. R. Frackelton Jr. (2000)
Mol. Endocrinol. 14, 1649-1660
   Abstract »    Full Text »
Plasma Membrane Estrogen Receptors Are Coupled to Endothelial Nitric-oxide Synthase through Galpha i.
M. H. Wyckoff, K. L. Chambliss, C. Mineo, I. S. Yuhanna, M. E. Mendelsohn, S. M. Mumby, and P. W. Shaul (2001)
J. Biol. Chem. 276, 27071-27076
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882