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 Neill, J. D. Articles by Sellers, J. C. Search for Related Content PubMed PubMed Citation Articles by Neill, J. D. Articles by Sellers, J. C.

Potential Regulatory Roles for G Protein-Coupled Receptor Kinases and ß-Arrestins in Gonadotropin-Releasing Hormone Receptor Signaling¹

Department of Physiology and Biophysics, University of Alabama, Birmingham, Alabama 35294-0005

Address all correspondence and requests for reprints to: Jimmy D. Neill, Department of Physiology and Biophysics, BHSB 812, 1918 University Boulevard, University of Alabama, Birmingham, Alabama 35294-0005. E-mail: neill{at}uab.edu

GnRH stimulates gonadotropin secretion, which desensitizes unless the releasing hormone is secreted or administered in a pulsatile fashion. The mechanism of desensitization is unknown, but as the GnRH receptor is G protein coupled, it might involve G protein-coupled receptor kinases (GRKs). Such kinases phosphorylate the intracellular regions of seven-transmembrane receptors, permitting ß-arrestin to bind, which prevents the receptor from activating G proteins. Here, we tested the effect of GRKs and ß-arrestins on GnRH-induced inositol trisphosphate (IP₃) production in COS cells transfected with the GnRH receptor complementary DNA. GRK2, -3, and -6 overexpression inhibited IP₃ production by 50–75% during the 30 sec of GnRH treatment. Coexpression of GRK2 and ß-arrestin-2 suppressed GnRH-induced IP₃ production more than that of either alone. Immunocytochemical staining of rat anterior pituitary revealed that all cells expressed GRK2, -3, and -6; all cells also expressed the ß-arrestins. Western blots on cytosolic extracts of rat pituitaries revealed the presence of GRK2/3 and ß-arrestin-1 and -2. The expression of GRKs and ß-arrestins by gonadotropes and their inhibition of GnRH-stimulated IP₃ production in COS-1 cells expressing the GnRH receptor suggest a potential regulatory role for the GRK/ß arrestin paradigm in GnRH receptor signaling.

This article has been cited by other articles:

				J. Zhou, M. F. A. Livak, M. Bernier, D. C. Muller, O. D. Carlson, D. Elahi, S. Maudsley, and J. M. Egan Ubiquitination is involved in glucose-mediated downregulation of GIP receptors in islets Am J Physiol Endocrinol Metab, August 1, 2007; 293(2): E538 - E547. [Abstract] [Full Text] [PDF]

				B. W. Jones, G. J. Song, E. K. Greuber, and P. M. Hinkle Phosphorylation of the Endogenous Thyrotropin-releasing Hormone Receptor in Pituitary GH3 Cells and Pituitary Tissue Revealed by Phosphosite-specific Antibodies J. Biol. Chem., April 27, 2007; 282(17): 12893 - 12906. [Abstract] [Full Text] [PDF]

				A Hassan and D Mason Mechanisms of desensitization of the adrenocorticotropin response to arginine vasopressin in ovine anterior pituitary cells J. Endocrinol., January 1, 2005; 184(1): 29 - 40. [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]

				F. Lin, H.-y. Wang, and C. C. Malbon Gravin-mediated Formation of Signaling Complexes in beta 2-Adrenergic Receptor Desensitization and Resensitization J. Biol. Chem., June 16, 2000; 275(25): 19025 - 19034. [Abstract] [Full Text] [PDF]

				C.-C. Tseng and X.-Y. Zhang Role of G Protein-Coupled Receptor Kinases in Glucose-Dependent Insulinotropic Polypeptide Receptor Signaling Endocrinology, March 1, 2000; 141(3): 947 - 952. [Abstract] [Full Text] [PDF]

				A. Heding, M. Vrecl, A. C. Hanyaloglu, R. Sellar, P. L. Taylor, and K. A. Eidne The Rat Gonadotropin-Releasing Hormone Receptor Internalizes via a {beta}-Arrestin-Independent, but Dynamin-Dependent, Pathway: Addition of a Carboxyl-Terminal Tail Confers {beta}-Arrestin Dependency Endocrinology, January 1, 2000; 141(1): 299 - 306. [Abstract] [Full Text] [PDF]

				J. D. Neill, L. C. Musgrove, L. W. Duck, and J. C. Sellers High Efficiency Method for Gene Transfer in Normal Pituitary Gonadotropes: Adenoviral-Mediated Expression of G Protein-Coupled Receptor Kinase 2 Suppresses Luteinizing Hormone Secretion Endocrinology, June 1, 1999; 140(6): 2562 - 2569. [Abstract] [Full Text]

				M. Bunemann and M M. Hosey G-protein coupled receptor kinases as modulators of G-protein signalling J. Physiol., May 15, 1999; 517(1): 5 - 23. [Abstract] [Full Text] [PDF]

				X. Lin, J. A. Janovick, and P. M. Conn Mutations at the Consensus Phosphorylation Sites in the Third Intracellular Loop of the Rat Gonadotropin-Releasing Hormone Receptor: Effects on Receptor Ligand Binding and Signal Transduction Biol Reprod, December 1, 1998; 59(6): 1470 - 1476. [Abstract] [Full Text]