The human gonadotropin releasing hormone type I receptor is a functional intracellular GPCR expressed on the nuclear membrane.
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 ineffi...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2010-07-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC2900216?pdf=render |
| _version_ | 1818538662022873088 |
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| author | Michelle Re Macarena Pampillo Martin Savard Céléna Dubuc Craig A McArdle Robert P Millar P Michael Conn Fernand Gobeil Moshmi Bhattacharya Andy V Babwah |
| author_facet | Michelle Re Macarena Pampillo Martin Savard Céléna Dubuc Craig A McArdle Robert P Millar P Michael Conn Fernand Gobeil Moshmi Bhattacharya Andy V Babwah |
| author_sort | Michelle Re |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-11T21:31:50Z |
| format | Article |
| id | doaj.art-0d60d3ede10340949374b541eaa8c83f |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-11T21:31:50Z |
| publishDate | 2010-07-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-0d60d3ede10340949374b541eaa8c83f2022-12-22T00:50:08ZengPublic Library of Science (PLoS)PLoS ONE1932-62032010-07-0157e1148910.1371/journal.pone.0011489The human gonadotropin releasing hormone type I receptor is a functional intracellular GPCR expressed on the nuclear membrane.Michelle ReMacarena PampilloMartin SavardCéléna DubucCraig A McArdleRobert P MillarP Michael ConnFernand GobeilMoshmi BhattacharyaAndy V BabwahThe 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.http://europepmc.org/articles/PMC2900216?pdf=render |
| spellingShingle | Michelle Re Macarena Pampillo Martin Savard Céléna Dubuc Craig A McArdle Robert P Millar P Michael Conn Fernand Gobeil Moshmi Bhattacharya Andy V Babwah The human gonadotropin releasing hormone type I receptor is a functional intracellular GPCR expressed on the nuclear membrane. PLoS ONE |
| title | The human gonadotropin releasing hormone type I receptor is a functional intracellular GPCR expressed on the nuclear membrane. |
| title_full | The human gonadotropin releasing hormone type I receptor is a functional intracellular GPCR expressed on the nuclear membrane. |
| title_fullStr | The human gonadotropin releasing hormone type I receptor is a functional intracellular GPCR expressed on the nuclear membrane. |
| title_full_unstemmed | The human gonadotropin releasing hormone type I receptor is a functional intracellular GPCR expressed on the nuclear membrane. |
| title_short | The human gonadotropin releasing hormone type I receptor is a functional intracellular GPCR expressed on the nuclear membrane. |
| title_sort | human gonadotropin releasing hormone type i receptor is a functional intracellular gpcr expressed on the nuclear membrane |
| url | http://europepmc.org/articles/PMC2900216?pdf=render |
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