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Dominant-Negative Action of Disease-Causing Gonadotropin-Releasing Hormone Receptor (GnRHR) Mutants: A Trait That Potentially Coevolved with Decreased Plasma Membrane Expression of GnRHR in Humans

Oregon Health and Science University (A.L.-M., A.U.-A., J.A.J., P.M.C.), Portland, Oregon 97239-3098; Oregon National Primate Research Center (A.L.-M., A.U.-A., J.A.J., P.M.C.), Beaverton, Oregon 97006; Research Unit in Reproductive Medicine, Instituto Mexicano del Seguro Social (A.L.-M., A.U.-A., P.M.C.), México D.F., C.P. 10101, México; and Department of Chemistry, University of Kentucky (T.H.J.), Lexington, Kentucky 40506-0055

Address all correspondence and requests for reprints to: Dr. Michael Conn, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239-3098. E-mail: connm{at}ohsu.edu.

Loss of function by 11 of 13 naturally occurring mutations in the human GnRH receptor (hGnRHR) was thought to result from impaired ligand binding or effector coupling, but actually results from receptor misrouting. Homo- or heterodimerization of mutant receptors with wild-type (WT) receptors occurs for other G protein-coupled receptors and may result in dominant-negative or -positive effects on the WT receptor. We tested the hypothesis that WT hGnRHR function was affected by misfolded hGnRHR mutants. hGnRHR mutants were found to inhibit the function of WT GnRHR (measured by activation of effector and ligand binding). Inhibition varied depending on the particular hGnRHR mutant coexpressed and the ratio of hGnRHR mutant to WT hGnRHR cDNA cotransfected. The hGnRHR mutants did not interfere with the function of genetically modified hGnRHRs bearing either a deletion of primate-specific Lys¹⁹¹ or the carboxyl-terminal tail of the catfish GnRHR; these show intrinsically enhanced expression. Moreover, a peptidomimetic antagonist of GnRH enhanced the expression of WT hGnRHR, but not of genetically modified hGnRHR species. The dominant-negative effect of the naturally occurring receptor mutants occurred only for the WT hGnRHR, which has intrinsic low maturation efficiency. The data suggest that this dominant negative effect accompanies the diminished plasma membrane expression as a recent evolutionary event.

This work was supported by NIH Grants HD-19899, RR-00163, HD-18185, and TW/HD-00668.

Abbreviations: cfCtail, Catfish carboxyl-terminal tail chimera; GPCR, G protein-coupled receptor; hGnRHR, human GnRH receptor; IP, inositol phosphate; WT, wild type.

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