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XB-ART-41785
PLoS One July 23, 2010; 5 (7): e11489.

The human gonadotropin releasing hormone type I receptor is a functional intracellular GPCR expressed on the nuclear membrane.

Re M , Pampillo M , Savard M , Dubuc C , McArdle CA , Millar RP , Conn PM , Gobeil F , Bhattacharya M , Babwah AV .


Abstract
The mammalian type I gonadotropin releasing hormone receptor (GnRH-R) is a structurally unique G protein-coupled receptor (GPCR) that lacks cytoplasmic tail sequences and displays inefficient plasma membrane expression (PME). Compared to its murine counterparts, the primate type I receptor is inefficiently folded and retained in the endoplasmic reticulum (ER) leading to a further reduction in PME. The decrease in PME and concomitant increase in intracellular localization of the mammalian GnRH-RI led us to characterize the spatial distribution of the human and mouse GnRH receptors in two human cell lines, HEK 293 and HTR-8/SVneo. In both human cell lines we found the receptors were expressed in the cytoplasm and were associated with the ER and nuclear membrane. A molecular analysis of the receptor protein sequence led us to identify a putative monopartite nuclear localization sequence (NLS) in the first intracellular loop of GnRH-RI. Surprisingly, however, neither the deletion of the NLS nor the addition of the Xenopus GnRH-R cytoplasmic tail sequences to the human receptor altered its spatial distribution. Finally, we demonstrate that GnRH treatment of nuclei isolated from HEK 293 cells expressing exogenous GnRH-RI triggers a significant increase in the acetylation and phosphorylation of histone H3, thereby revealing that the nuclear-localized receptor is functional. Based on our findings, we conclude that the mammalian GnRH-RI is an intracellular GPCR that is expressed on the nuclear membrane. This major and novel discovery causes us to reassess the signaling potential of this physiologically and clinically important receptor.

PubMed ID: 20628612
PMC ID: PMC2900216
Article link: PLoS One
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: canx cltc cstb gnrh1 golga2 gprc6a lmna


Article Images: [+] show captions
References [+] :
Arora, Effects of second intracellular loop mutations on signal transduction and internalization of the gonadotropin-releasing hormone receptor. 1995, Pubmed