HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 280, Issue 26, 24506-24514, July 1, 2005

This Article Full Text Full Text (PDF) All Versions of this Article: 280/26/24506    most recent M501978200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted 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 Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Knollman, P. E. Articles by Conn, P. M. Search for Related Content PubMed PubMed Citation Articles by Knollman, P. E. Articles by Conn, P. M. Social Bookmarking                      What's this?

Parallel Regulation of Membrane Trafficking and Dominant-negative Effects by Misrouted Gonadotropin-releasing Hormone Receptor Mutants^*

Paul E. Knollman, Jo Ann Janovick, Shaun P. Brothers, and P. Michael Conn¶||

From the Divisions of Neuroscience and Reproductive Biology, Oregon National Primate Research Center and Department of Physiology and Pharmacology and ^¶Cell and Developmental Biology, Oregon Health and Science University, Beaverton, Oregon 97006

Gonadotropin-releasing hormone (GnRH) receptor mutants from patients with hypogonadotropic hypogonadism are frequently misrouted proteins that exert a dominant-negative (DN) effect on human (h) wild-type (WT) receptor, due to oligomerization and retention in the endoplasmic reticulum. Pharmacologic chaperones restore correct folding, rescuing mutants and WT receptor from this oligomer. Rat WT retains the ability to oligomerize (since human and mouse mutants exert a DN effect on rat (r) WT sequence) but, unlike human or mouse, escapes the DN effect of GnRH receptor (Gn-RHR) mutants because rGnRHR mutants route to the plasma membrane with higher efficiency than mouse or human mutants. These distinct behaviors of mouse and rat GnRHRs (distinguished by only four semi- or non-conservative amino acid differences) led us to assess the role of each amino acid. The difference in both routing and the DN effect appears mediated primarily by Ser²¹⁶ in the rGnRHR. The homologous amino acid in the hGn-RHR is also Ser and is compensated for by the primate-unique insertion of Lys¹⁹¹ that, alone, dramatically decreases routing of the receptor. These studies establish the relation between the DN effect and altered receptor trafficking and explain why hGnRHR is more susceptible to defective trafficking by disease-related point mutations than rodent counterparts.

Received for publication, February 22, 2005 , and in revised form, May 9, 2005.

^* This work was supported by National Institutes of Health Grants HD-19899, RR-00163, and HD-18185. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: ONPRC/OHSU, 505 NW 185th Ave., Beaverton, OR 97006. Tel.: 503-690-5297; Fax: 503-690-5569; E-mail: connm{at}ohsu.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				E. Jardon-Valadez, A. Aguilar-Rojas, G. Maya-Nunez, A. Leanos-Miranda, A. Pineiro, P M. Conn, and A. Ulloa-Aguirre Conformational effects of Lys191 in the human GnRH receptor: mutagenesis and molecular dynamics simulations studies J. Endocrinol., May 1, 2009; 201(2): 297 - 307. [Abstract] [Full Text] [PDF]

				J. A. Janovick, A. Patny, R. Mosley, M. T. Goulet, M. D. Altman, T. S. Rush III, A. Cornea, and P. M. Conn Molecular Mechanism of Action of Pharmacoperone Rescue of Misrouted GPCR Mutants: The GnRH Receptor Mol. Endocrinol., February 1, 2009; 23(2): 157 - 168. [Abstract] [Full Text] [PDF]

				A. R Finch, K. R Sedgley, C. J Caunt, and C. A McArdle Plasma membrane expression of GnRH receptors: regulation by antagonists in breast, prostate, and gonadotrope cell lines J. Endocrinol., February 1, 2008; 196(2): 353 - 367. [Abstract] [Full Text] [PDF]

				M. A. Bedoukian, J. D. Whitesell, E. J. Peterson, C. M. Clay, and K. M. Partin The Stargazin C Terminus Encodes an Intrinsic and Transferable Membrane Sorting Signal J. Biol. Chem., January 18, 2008; 283(3): 1597 - 1600. [Abstract] [Full Text] [PDF]

				P. M. Conn, A. Ulloa-Aguirre, J. Ito, and J. A. Janovick G Protein-Coupled Receptor Trafficking in Health and Disease: Lessons Learned to Prepare for Therapeutic Mutant Rescue in Vivo Pharmacol. Rev., September 1, 2007; 59(3): 225 - 250. [Abstract] [Full Text] [PDF]

				Z.-L. Lu, M. Coetsee, C. D. White, and R. P. Millar Structural Determinants for Ligand-Receptor Conformational Selection in a Peptide G Protein-coupled Receptor J. Biol. Chem., June 15, 2007; 282(24): 17921 - 17929. [Abstract] [Full Text] [PDF]

				J. A. Janovick, S. P. Brothers, P. E. Knollman, and P. M. Conn Specializations of a G-protein-coupled receptor that appear to aid with detection of frequency-modulated signals from its ligand FASEB J, February 1, 2007; 21(2): 384 - 392. [Abstract] [Full Text] [PDF]

				S. P Brothers, J. A. Janovick, and P M. Conn Calnexin regulated gonadotropin-releasing hormone receptor plasma membrane expression J. Mol. Endocrinol., December 1, 2006; 37(3): 479 - 488. [Abstract] [Full Text] [PDF]

				K. R Sedgley, A. R Finch, C. J Caunt, and C. A McArdle Intracellular gonadotropin-releasing hormone receptors in breast cancer and gonadotrope lineage cells J. Endocrinol., December 1, 2006; 191(3): 625 - 636. [Abstract] [Full Text] [PDF]

				P. M. Conn, P. E. Knollman, S. P. Brothers, and J. A. Janovick Protein Folding as Posttranslational Regulation: Evolution of a Mechanism for Controlled Plasma Membrane Expression of a G Protein-Coupled Receptor Mol. Endocrinol., December 1, 2006; 20(12): 3035 - 3041. [Abstract] [Full Text] [PDF]

				F. Cerrato, J. Shagoury, M. Kralickova, A. Dwyer, J. Falardeau, M. Ozata, G. Van Vliet, P. Bouloux, J. E Hall, F. J Hayes, et al. Coding sequence analysis of GNRHR and GPR54 in patients with congenital and adult-onset forms of hypogonadotropic hypogonadism Eur. J. Endocrinol., November 1, 2006; 155(suppl_1): S3 - S10. [Abstract] [Full Text] [PDF]

				P M. Conn, J. A. Janovick, S. P Brothers, and P. E Knollman 'Effective inefficiency': cellular control of protein trafficking as a mechanism of post-translational regulation. J. Endocrinol., July 1, 2006; 190(1): 13 - 16. [Abstract] [Full Text] [PDF]

				S. R. Hawtin Pharmacological Chaperone Activity of SR49059 to Functionally Recover Misfolded Mutations of the Vasopressin V1a Receptor J. Biol. Chem., May 26, 2006; 281(21): 14604 - 14614. [Abstract] [Full Text] [PDF]

				J. A. Janovick, P. E. Knollman, S. P. Brothers, R. Ayala-Yanez, A. S. Aziz, and P. M. Conn Regulation of G Protein-coupled Receptor Trafficking by Inefficient Plasma Membrane Expression: MOLECULAR BASIS OF AN EVOLVED STRATEGY J. Biol. Chem., March 31, 2006; 281(13): 8417 - 8425. [Abstract] [Full Text] [PDF]