This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Troispoux, C. Articles by Reiter, E. Search for Related Content PubMed PubMed Citation Articles by Troispoux, C. Articles by Reiter, E.

Involvement of G Protein-Coupled Receptor Kinases and Arrestins in Desensitization to Follicle-Stimulating Hormone Action

INRA/CNRS URA 1291 (C.T., F.G., Y.C., E.R.) Station de Physiologie de la Reproduction des Mammifères Domestiques 37380 Nouzilly, France
Département de Biologie Cellulaire et Moléculaire (J.-M.E., D.F.) Service de Biologie Cellulaire CEA Saclay 91191 Gif-sur-Yvette Cedex, France
Consorzio Mario Negri Sud (L.I., A.D.B.) Istituto di Ricerche Farmacologiche "Mario Negri" 66030 Santa Maria Imbaro, Italy

FSH rapidly desensitizes the FSH-receptor (FSH-R) upon binding. Very little information is available concerning the regulatory proteins involved in this process. In the present study, we investigated whether G protein-coupled receptor kinases (GRKs) and arrestins have a role in FSH-R desensitization, using a mouse Ltk 7/12 cell line stably overexpressing the rat FSH-R as a model. We found that these cells, which express GRK2, GRK3, GRK5, and GRK6 as well as ß-arrestins 1 and 2 as detected by RT-PCR and by Western blotting, were rapidly desensitized in the presence of FSH. Overexpression of GRKs and/or ß-arrestins in Ltk 7/12 cells allowed us to demonstrate 1) that GRK2, -3, -5, -6a, and -6b inhibit the FSH-R-mediated signaling (from 71% to 96% of maximal inhibition depending on the kinase, P < 0.001); 2) that ß-arrestins 1 or 2 also decrease the FSH action when overexpressed (80% of maximal inhibition, P < 0.01) whereas dominant negative ß-arrestin 2 [319–418] potentiates it 8-fold (P < 0.001); 3) that ß-arrestins and GRKs (except GRK6a) exert additive inhibition on FSH-induced response; and 4) that FSH-R desensitization depends upon the endogenous expression of GRKs, since there is potentiation of the FSH response (2- to 3-fold, P < 0.05) with antisenses cDNAs for GRK2, -5, and -6, but not GRK3. Our results show that the desensitization of the FSH-induced response involves the GRK/arrestin system.

This article has been cited by other articles:

				E. Kara, P. Crepieux, C. Gauthier, N. Martinat, V. Piketty, F. Guillou, and E. Reiter A Phosphorylation Cluster of Five Serine and Threonine Residues in the C-Terminus of the Follicle-Stimulating Hormone Receptor Is Important for Desensitization But Not for ss-Arrestin-Mediated ERK Activation Mol. Endocrinol., November 1, 2006; 20(11): 3014 - 3026. [Abstract] [Full Text] [PDF]

				S. Marion, E. Kara, P. Crepieux, V. Piketty, N. Martinat, F. Guillou, and E. Reiter G protein-coupled receptor kinase 2 and {beta}-arrestins are recruited to FSH receptor in stimulated rat primary Sertoli cells. J. Endocrinol., August 1, 2006; 190(2): 341 - 350. [Abstract] [Full Text] [PDF]

				R. Frenzel, C. Voigt, and R. Paschke The Human Thyrotropin Receptor Is Predominantly Internalized by {beta}-Arrestin 2 Endocrinology, June 1, 2006; 147(6): 3114 - 3122. [Abstract] [Full Text] [PDF]

				F. Otsuka, R. K. Moore, X. Wang, S. Sharma, T. Miyoshi, and S. Shimasaki Essential Role of the Oocyte in Estrogen Amplification of Follicle-Stimulating Hormone Signaling in Granulosa Cells Endocrinology, August 1, 2005; 146(8): 3362 - 3367. [Abstract] [Full Text] [PDF]

				W. H Walker and J. Cheng FSH and testosterone signaling in Sertoli cells Reproduction, July 1, 2005; 130(1): 15 - 28. [Abstract] [Full Text] [PDF]

				B. D. Cohen, J. T. Bariteau, L. M. Magenis, and J. A. Dias Regulation of Follitropin Receptor Cell Surface Residency by the Ubiquitin-Proteasome Pathway Endocrinology, October 1, 2003; 144(10): 4393 - 4402. [Abstract] [Full Text] [PDF]

				N. Fernandez, F. Monczor, B. Lemos, C. Notcovich, A. Baldi, C. Davio, and C. Shayo Reduction of G Protein-Coupled Receptor Kinase 2 Expression in U-937 Cells Attenuates H2 Histamine Receptor Desensitization and Induces Cell Maturation Mol. Pharmacol., December 1, 2002; 62(6): 1506 - 1514. [Abstract] [Full Text] [PDF]

				R. Gaudreau, C. Le Gouill, M.-H. Venne, J. Stankova, and M. Rola-Pleszczynski Threonine 308 within a Putative Casein Kinase 2 Site of the Cytoplasmic Tail of Leukotriene B4 Receptor (BLT1) Is Crucial for Ligand-induced, G-protein-coupled Receptor-specific Kinase 6-mediated Desensitization J. Biol. Chem., August 23, 2002; 277(35): 31567 - 31576. [Abstract] [Full Text] [PDF]

				S. Mukherjee, V. V. Gurevich, A. Preninger, H. E. Hamm, M.-F. Bader, A. T. Fazleabas, L. Birnbaumer, and M. Hunzicker-Dunn Aspartic Acid 564 in the Third Cytoplasmic Loop of the Luteinizing Hormone/Choriogonadotropin Receptor Is Crucial for Phosphorylation-independent Interaction with Arrestin2 J. Biol. Chem., May 10, 2002; 277(20): 17916 - 17927. [Abstract] [Full Text] [PDF]

				S. Marion, F. Robert, P. Crepieux, N. Martinat, C. Troispoux, F. Guillou, and E. Reiter G Protein-Coupled Receptor Kinases and Beta Arrestins Are Relocalized and Attenuate Cyclic 3',5'-Adenosine Monophosphate Response to Follicle-Stimulating Hormone in Rat Primary Sertoli Cells Biol Reprod, January 1, 2002; 66(1): 70 - 76. [Abstract] [Full Text]

				S. Hilairet, C. Belanger, J. Bertrand, A. Laperriere, S. M. Foord, and M. Bouvier Agonist-promoted Internalization of a Ternary Complex between Calcitonin Receptor-like Receptor, Receptor Activity-modifying Protein 1 (RAMP1), and beta -Arrestin J. Biol. Chem., November 2, 2001; 276(45): 42182 - 42190. [Abstract] [Full Text] [PDF]

				F. M. Dautzenberg, S. Braun, and R. L. Hauger GRK3 mediates desensitization of CRF1 receptors: a potential mechanism regulating stress adaptation Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2001; 280(4): R935 - R946. [Abstract] [Full Text] [PDF]

				S. L. Ferrari and A. Bisello Cellular Distribution of Constitutively Active Mutant Parathyroid Hormone (PTH)/PTH-Related Protein Receptors and Regulation of Cyclic Adenosine 3',5'-Monophosphate Signaling by {beta}-Arrestin2 Mol. Endocrinol., January 1, 2001; 15(1): 149 - 163. [Abstract] [Full Text]

				A. P. N. Themmen and I. T. Huhtaniemi Mutations of Gonadotropins and Gonadotropin Receptors: Elucidating the Physiology and Pathophysiology of Pituitary-Gonadal Function Endocr. Rev., October 1, 2000; 21(5): 551 - 583. [Abstract] [Full Text]

				B. Hennuy, E. Reiter, A. Cornet, M. Bruyninx, M. Daukandt, P. Houssa, V.-H. N'Guyen, J. Closset, and G. Hennen A Novel Messenger Ribonucleic Acid Homologous to Human MAGE-D Is Strongly Expressed in Rat Sertoli Cells and Weakly in Leydig Cells and Is Regulated by Follitropin, Lutropin, and Prolactin Endocrinology, October 1, 2000; 141(10): 3821 - 3831. [Abstract] [Full Text] [PDF]

				S. A. Laporte, R. H. Oakley, J. A. Holt, L. S. Barak, and M. G. Caron The Interaction of beta -Arrestin with the AP-2 Adaptor Is Required for the Clustering of beta 2-Adrenergic Receptor into Clathrin-coated Pits J. Biol. Chem., July 21, 2000; 275(30): 23120 - 23126. [Abstract] [Full Text] [PDF]

				R. B. Penn, R. M. Pascual, Y.-M. Kim, S. J. Mundell, V. P. Krymskaya, R. A. Panettieri Jr., and J. L. Benovic Arrestin Specificity for G Protein-coupled Receptors in Human Airway Smooth Muscle J. Biol. Chem., August 24, 2001; 276(35): 32648 - 32656. [Abstract] [Full Text] [PDF]