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Divisions of Neuroscience (S.P.B., A.C., J.A.J., P.M.C.) and Reproductive Biology (P.M.C.), Oregon National Primate Research Center and Departments of Physiology and Pharmacology (S.P.B., A.C., J.A.J., P.M.C.) and Cell and Developmental Biology (P.M.C.), Oregon Health and Science University, Beaverton, Oregon 97006
Address all correspondence and requests for reprints to: P. Michael Conn, Oregon National Primate Research Center/Oregon Health and Science University, 505 Northwest 185th Avenue, Beaverton, Oregon 97006. E-mail: connm{at}ohsu.edu.
The GnRH receptor (GnRHR) is a heptahelical G protein-coupled receptor found in the plasma membrane of pituitary gonadotropes. GnRHR mutants isolated from patients with hypogonadotropic hypogonadism (HH) are frequently mislocalized proteins that can be restored to function by pharmacological chaperones. Nonfunctional HH mutants inhibit ligand binding and ligand-activated second messenger production by wild-type (WT) receptor when both are coexpressed in vitro. In this study, confocal microscopy of fluorescently labeled GnRHR was used to show that the dominant-negative effect, which occurs for human (but not for rodent) GnRHR, results from WT receptor retention in the endoplasmic reticulum by mislocalized mutants. Mutants hGnRHR(E90K), hGnRHR(L266R), and hGnRHR(S168R) were selected for study because they are known to be fully rescuable, partially rescuable, or nonrescuable (respectively) by a specific pharmacological chaperone. This chaperone corrects folding errors and promotes correct intracellular routing. Using this drug we showed that correcting routing of the mutant protein also rescues the WT receptor. Because of the large number of human diseases that appear to be caused by defective protein folding and subsequent mislocalization, it is likely that endoplasmic reticulum retention is a common cause of dominant-negative actions for other diseases involving G protein-coupled receptors, as appears to be the case in HH and for which there exists a potential therapeutic agent.
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