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J. Biol. Chem., Vol. 281, Issue 13, 8417-8425, March 31, 2006

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Regulation of G Protein-coupled Receptor Trafficking by Inefficient Plasma Membrane Expression

MOLECULAR BASIS OF AN EVOLVED STRATEGY^*

Jo Ann Janovick, Paul E. Knollman, Shaun P. Brothers, Rodrigo Ayala-Yáñez, Abeer S. Aziz, and P. Michael Conn^¶1

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

Despite the prevalence of G protein-coupled receptors as transducers of signals from hormones, neurotransmitters, odorants, and light, little is known about mechanisms that regulate their plasma membrane expression (PME), although misfolded receptors are recognized and retained by a cellular quality control system (QCS). Convergent evolution of the gonadotropin-releasing hormone (GnRH) receptor (GnRHR) progressively decreases inositol phosphate production in response to agonist, validated as a measure of PME of receptor. A pharmacological chaperone that optimizes folding also increases PME of human, but not of rat or mouse, GnRHR because a higher percentage of human GnRHRs are misfolded structures due to their failure to form an apparent sulfhydryl bridge, and they are retained by the QCS. Bridge formation is increased by deleting (primate-specific) Lys¹⁹¹. In rat or mouse GnRHR that lacks Lys¹⁹¹, the bridge is non-essential and receptor is efficiently routed to the plasma membrane. Addition of Lys¹⁹¹ alone to the rat sequence did not diminish PME, indicating that other changes are required for its effects. A strategy, based on identification of amino acids that both 1) co-evolved with the Lys¹⁹¹ and 2) were thermodynamically unfavorable substitutions, identified motifs in multiple domains of the human receptor that control the destabilizing influence of Lys¹⁹¹ on a particular Cys bridge, resulting in diminished PME. The data show a novel and underappreciated means of posttranslational control of a G protein-coupled receptor by altering its interaction with the QCS and provide a biochemical explanation of the basis of disease-causing mutations of this receptor.

Received for publication, September 28, 2005 , and in revised form, January 27, 2006.

^* This work was supported by National Institutes of Health Grants HD-19899, RR-00163, TW/HD-00668, 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.

¹ 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.

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