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This version published online on March 10, 2005
Endocrinology, doi:10.1210/en.2005-0133
A more recent version of this article appeared on June 1, 2005
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Submitted on February 3, 2005
Accepted on February 28, 2005

Inhibition of Human Type I Gonadotropin-releasing Hormone Receptor (GnRHR-I) Function by Expression of a Human Type II GnRHR Gene Fragment

Adam J. Pawson*, Stuart Maudsley, Kevin Morgan, Lindsay Davidson, Zvi Naor, and Robert P. Millar

Human Reproductive Sciences Unit, Medical Research Council, Edinburgh, United Kingdom

* To whom correspondence should be addressed. E-mail: a.pawson{at}hrsu.mrc.ac.uk.

Humans possess only one functional GnRH receptor, the type I GnRH receptor (GnRHR-I). A type II GnRH receptor (GnRHR-II) gene homologue exists, but is disrupted by a frame shift and premature stop codon, suggesting that a conventional receptor is not translated from this gene. However, the gene remains transcriptionally active and displays alternative splicing. We have identified a putative translational start site 117-bp downstream of the premature stop codon. Utilization of this start codon encodes a protein (designated as the GnRHR-II-reliquum) corresponding to the domains from the cytoplasmic end of transmembrane domain (TMD)-5 to the carboxyl-terminus of the putative full-length receptor. Immunocytochemistry revealed that GnRHR-II-reliquum expression appeared to be localized throughout the cytoplasm. Transient co-transfection of GnRHR-I and GnRHR-II-reliquum constructs into COS-7 cells, resulted in reduced expression of the GnRHR-I at the cell-surface, and impaired signaling via the GnRHR-I as revealed by reduction of GnRH-induced inositol phosphate accumulation. This inhibitory effect was specific and dependent on the degree of GnRHR-II-reliquum co-expressed. Immunoblot analysis revealed that the total cell GnRHR-I complement, i.e. both cell-surface and nascent intracellular receptors, was markedly reduced by co-expression of the GnRHR-II-reliquum. Treatments with cell permeable agents that blocked either de novo protein synthesis (cyclohexamide) or proteinase-mediated degradation (leupeptin and PMSF) failed to alter the inhibitory effect of GnRHR-II-reliquum co-expression, suggesting that the inhibitory effect is exerted at the nucleus/endoplasmic reticulum or Golgi apparatus level, possibly by perturbing normal processing of GnRHR-I from these sites. We suggest that the GnRHR-II-reliquum plays a modulatory role in GnRHR-I expression.




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