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Submitted on March 3, 2004
Accepted on April 15, 2004
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
* To whom correspondence should be addressed. E-mail: connm{at}ohsu.edu.
The gonadotropin-releasing hormone receptor (GnRHR) is a heptahelical G protein coupled receptor (GPCR) 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. Non-functional HH mutants inhibit ligand binding and ligand activated second messenger production by wild type receptor when both are co-expressed in vitro. In this study, confocal microscopy of fluorescently labeled GnRHR was used to show that the "dominant-negative effect," that occurs for human (but not for rodent) GnRHR results from wild type 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 non-rescuable (respectively) by a specific pharmacological chaperone. This chaperone corrects folding errors and promotes correct intra-cellular routing. Using this drug we showed that correcting routing of the mutant protein, also rescues the wild type 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 GPCRs, as appears to be the case in HH and for which there exists a potential therapeutic agent.
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