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 Ronacher, K. Articles by Katz, A. A. Search for Related Content PubMed PubMed Citation Articles by Ronacher, K. Articles by Katz, A. A.

Serine Residues 338 and 339 in the Carboxyl-Terminal Tail of the Type II Gonadotropin-Releasing Hormone Receptor Are Critical for ß-Arrestin-Independent Internalization

Medical Research Council Research Group for Receptor Biology (K.R., N.M., N.N., T.A., C.A.F., A.A.K.), Division of Medical Biochemistry, Faculty of Health Sciences, University of Cape Town, and Department of Medicine (C.A.F., N.M.), University of Cape Town and Groote Schuur Hospital, Observatory 7925, Cape Town, South Africa; and Human Reproductive Sciences Unit (A.J.P., R.P.M.), Medical Research Council, Edinburgh EH16 4SB, Scotland, United Kingdom

Address all correspondence and requests for reprints to: Dr. Arieh Katz, Medical Research Council Research Group for Receptor Biology, Division of Medical Biochemistry, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory 7925, South Africa. E-mail: katz{at}curie.uct.ac.za.

Cloned mammalian type II GnRH receptors have a carboxyl-terminal tail in contrast to the mammalian type I GnRH receptors, which uniquely lack a carboxyl-terminal tail. Because this domain mediates internalization of many serpentine receptors, the internalization pathway of the marmoset monkey type II GnRH receptor and the functional role of the carboxyl-terminal tail in internalization was studied. The internalization pathway of the type II GnRH receptor was investigated in COS-1 cells by coexpressing G protein-coupled receptor kinases (GRKs), dynamin-1, and ß-arrestins. Internalization of the receptor requires GRKs and dynamin but does not require ß-arrestin. The type II GnRH receptor can also internalize via ß-arrestin in the presence of exogenous ß-arrestins, suggesting that the receptor can use two distinct internalization pathways. Receptor internalization appears to occur via clathrin-coated pits and caveolae because disruption of either structure inhibits internalization. Progressive truncations of the carboxyl-terminal tail identified a region containing serine residues 338 and 339 as critical for receptor internalization. Substitution of these serine residues with alanine residues inhibited internalization, whereas substitutions with glutamic acid residues rescued internalization. Furthermore, a dominant-negative GRK2 did not inhibit internalization of receptors having these serine substitutions, although it inhibited internalization of the wild-type receptor. These results together identify serine residues 338 and 339 in the carboxyl-terminal tail as critical for internalization of the type II GnRH receptor and suggest that these residues undergo phosphorylation by GRKs. However, neither of these residues, nor the carboxyl-terminal tail, is required for ß-arrestin-dependent internalization.

This article has been cited by other articles:

				A. J. Pawson, E. Faccenda, S. Maudsley, Z.-L. Lu, Z. Naor, and R. P. Millar Mammalian Type I Gonadotropin-Releasing Hormone Receptors Undergo Slow, Constitutive, Agonist-Independent Internalization Endocrinology, March 1, 2008; 149(3): 1415 - 1422. [Abstract] [Full Text] [PDF]

				B. Faurholm, S. Cochrane, R. R Millar, and A. A Katz Gene structure and promoter functional analysis of the marmoset type II GnRH receptor J. Mol. Endocrinol., August 1, 2007; 39(2): 91 - 104. [Abstract] [Full Text] [PDF]

				M R Silver and S A Sower Functional characterization and kinetic studies of an ancestral lamprey GnRH-III selective type II GnRH receptor from the sea lamprey, Petromyzon marinus. J. Mol. Endocrinol., June 1, 2006; 36(3): 601 - 610. [Abstract] [Full Text] [PDF]

				A. M. Navratil, T. A. Farmerie, J. Bogerd, T. M. Nett, and C. M. Clay Differential Impact of Intracellular Carboxyl Terminal Domains on Lipid Raft Localization of the Murine Gonadotropin-Releasing Hormone Receptor Biol Reprod, May 1, 2006; 74(5): 788 - 797. [Abstract] [Full Text] [PDF]

				J. N Hislop, C. J Caunt, K. R Sedgley, E. Kelly, S. Mundell, L. D Green, and C. A McArdle Internalization of gonadotropin-releasing hormone receptors (GnRHRs): does arrestin binding to the C-terminal tail target GnRHRs for dynamin-dependent internalization? J. Mol. Endocrinol., August 1, 2005; 35(1): 177 - 189. [Abstract] [Full Text] [PDF]