The Succinate Receptor SUCNR1 Resides at the Endoplasmic Reticulum and Relocates to the Plasma Membrane in Hypoxic Conditions
The GPCR SUCNR1/GPR91 exerts proangiogenesis upon stimulation with the Krebs cycle metabolite succinate. GPCR signaling depends on the surrounding environment and intracellular localization through location bias. Here, we show by microscopy and by cell fractionation that in neurons, SUCNR1 resides a...
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MDPI AG
2022-07-01
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| Online Access: | https://www.mdpi.com/2073-4409/11/14/2185 |
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| author | Melanie Sanchez David Hamel Emmanuel Bajon François Duhamel Vikrant K. Bhosle Tang Zhu Jose Carlos Rivera Rabah Dabouz Mathieu Nadeau-Vallée Nicholas Sitaras David-Étienne Tremblay Samy Omri Tiffany Habelrih Raphael Rouget Xin Hou Fernand Gobeil Jean-Sébastien Joyal Przemyslaw Sapieha Grant Mitchell Alfredo Ribeiro-Da-Silva Mohammad Ali Mohammad Nezhady Sylvain Chemtob |
| author_facet | Melanie Sanchez David Hamel Emmanuel Bajon François Duhamel Vikrant K. Bhosle Tang Zhu Jose Carlos Rivera Rabah Dabouz Mathieu Nadeau-Vallée Nicholas Sitaras David-Étienne Tremblay Samy Omri Tiffany Habelrih Raphael Rouget Xin Hou Fernand Gobeil Jean-Sébastien Joyal Przemyslaw Sapieha Grant Mitchell Alfredo Ribeiro-Da-Silva Mohammad Ali Mohammad Nezhady Sylvain Chemtob |
| author_sort | Melanie Sanchez |
| collection | DOAJ |
| description | The GPCR SUCNR1/GPR91 exerts proangiogenesis upon stimulation with the Krebs cycle metabolite succinate. GPCR signaling depends on the surrounding environment and intracellular localization through location bias. Here, we show by microscopy and by cell fractionation that in neurons, SUCNR1 resides at the endoplasmic reticulum (ER), while being fully functional, as shown by calcium release and the induction of the expression of the proangiogenic gene for VEGFA. ER localization was found to depend upon N-glycosylation, particularly at position N8; the nonglycosylated mutant receptor localizes at the plasma membrane shuttled by RAB11. This SUCNR1 glycosylation is physiologically regulated, so that during hypoxic conditions, SUCNR1 is deglycosylated and relocates to the plasma membrane. Downstream signal transduction of SUCNR1 was found to activate the prostaglandin synthesis pathway through direct interaction with COX-2 at the ER; pharmacologic antagonism of the PGE<sub>2</sub> EP<sub>4</sub> receptor (localized at the nucleus) was found to prevent VEGFA expression. Concordantly, restoring the expression of SUCNR1 in the retina of SUCNR1-null mice renormalized vascularization; this effect is markedly diminished after transfection of the plasma membrane-localized SUCNR1 N8A mutant, emphasizing that ER localization of the succinate receptor is necessary for proper vascularization. These findings uncover an unprecedented physiologic process where GPCR resides at the ER for signaling function. |
| first_indexed | 2024-03-09T03:35:09Z |
| format | Article |
| id | doaj.art-08718907106b4199a8f209beb94c4878 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-09T03:35:09Z |
| publishDate | 2022-07-01 |
| publisher | MDPI AG |
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| series | Cells |
| spelling | doaj.art-08718907106b4199a8f209beb94c48782023-12-03T14:49:45ZengMDPI AGCells2073-44092022-07-011114218510.3390/cells11142185The Succinate Receptor SUCNR1 Resides at the Endoplasmic Reticulum and Relocates to the Plasma Membrane in Hypoxic ConditionsMelanie Sanchez0David Hamel1Emmanuel Bajon2François Duhamel3Vikrant K. Bhosle4Tang Zhu5Jose Carlos Rivera6Rabah Dabouz7Mathieu Nadeau-Vallée8Nicholas Sitaras9David-Étienne Tremblay10Samy Omri11Tiffany Habelrih12Raphael Rouget13Xin Hou14Fernand Gobeil15Jean-Sébastien Joyal16Przemyslaw Sapieha17Grant Mitchell18Alfredo Ribeiro-Da-Silva19Mohammad Ali Mohammad Nezhady20Sylvain Chemtob21Department of Pharmacology and Therapeutics, McGill University, Montréal, QC H3A 1A3, CanadaDepartment of Pharmacology, Université de Montréal, Montréal, QC H3C 3J7, CanadaDepartment of Pediatrics, Research Center-CHU Ste-Justine, Montréal, QC H3T 1C5, CanadaDepartment of Pharmacology, Université de Montréal, Montréal, QC H3C 3J7, CanadaDepartment of Pharmacology and Therapeutics, McGill University, Montréal, QC H3A 1A3, CanadaDepartment of Pediatrics, Research Center-CHU Ste-Justine, Montréal, QC H3T 1C5, CanadaDepartment of Ophthalmology, Research Center of Hôpital Maisonneuve-Rosemont, Université de Montréal, Montréal, QC H1T 2M4, CanadaDepartment of Pharmacology and Therapeutics, McGill University, Montréal, QC H3A 1A3, CanadaDepartment of Pharmacology, Université de Montréal, Montréal, QC H3C 3J7, CanadaDepartment of Pharmacology, Université de Montréal, Montréal, QC H3C 3J7, CanadaDepartment of Pharmacology, Université de Montréal, Montréal, QC H3C 3J7, CanadaDepartment of Ophthalmology, Research Center of Hôpital Maisonneuve-Rosemont, Université de Montréal, Montréal, QC H1T 2M4, CanadaDepartment of Pharmacology, Université de Montréal, Montréal, QC H3C 3J7, CanadaDepartment of Pharmacology and Therapeutics, McGill University, Montréal, QC H3A 1A3, CanadaDepartment of Pediatrics, Research Center-CHU Ste-Justine, Montréal, QC H3T 1C5, CanadaDepartment of Pharmacology, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, CanadaDepartment of Pediatrics, Research Center-CHU Ste-Justine, Montréal, QC H3T 1C5, CanadaDepartment of Ophthalmology, Research Center of Hôpital Maisonneuve-Rosemont, Université de Montréal, Montréal, QC H1T 2M4, CanadaDepartment of Pediatrics, Research Center-CHU Ste-Justine, Montréal, QC H3T 1C5, CanadaDepartment of Pharmacology and Therapeutics, McGill University, Montréal, QC H3A 1A3, CanadaDepartment of Pediatrics, Research Center-CHU Ste-Justine, Montréal, QC H3T 1C5, CanadaDepartment of Pharmacology and Therapeutics, McGill University, Montréal, QC H3A 1A3, CanadaThe GPCR SUCNR1/GPR91 exerts proangiogenesis upon stimulation with the Krebs cycle metabolite succinate. GPCR signaling depends on the surrounding environment and intracellular localization through location bias. Here, we show by microscopy and by cell fractionation that in neurons, SUCNR1 resides at the endoplasmic reticulum (ER), while being fully functional, as shown by calcium release and the induction of the expression of the proangiogenic gene for VEGFA. ER localization was found to depend upon N-glycosylation, particularly at position N8; the nonglycosylated mutant receptor localizes at the plasma membrane shuttled by RAB11. This SUCNR1 glycosylation is physiologically regulated, so that during hypoxic conditions, SUCNR1 is deglycosylated and relocates to the plasma membrane. Downstream signal transduction of SUCNR1 was found to activate the prostaglandin synthesis pathway through direct interaction with COX-2 at the ER; pharmacologic antagonism of the PGE<sub>2</sub> EP<sub>4</sub> receptor (localized at the nucleus) was found to prevent VEGFA expression. Concordantly, restoring the expression of SUCNR1 in the retina of SUCNR1-null mice renormalized vascularization; this effect is markedly diminished after transfection of the plasma membrane-localized SUCNR1 N8A mutant, emphasizing that ER localization of the succinate receptor is necessary for proper vascularization. These findings uncover an unprecedented physiologic process where GPCR resides at the ER for signaling function.https://www.mdpi.com/2073-4409/11/14/2185SUCNR1/GPR91succinateGPCRN-glycosylationendoplasmic reticulumangiogenesis |
| spellingShingle | Melanie Sanchez David Hamel Emmanuel Bajon François Duhamel Vikrant K. Bhosle Tang Zhu Jose Carlos Rivera Rabah Dabouz Mathieu Nadeau-Vallée Nicholas Sitaras David-Étienne Tremblay Samy Omri Tiffany Habelrih Raphael Rouget Xin Hou Fernand Gobeil Jean-Sébastien Joyal Przemyslaw Sapieha Grant Mitchell Alfredo Ribeiro-Da-Silva Mohammad Ali Mohammad Nezhady Sylvain Chemtob The Succinate Receptor SUCNR1 Resides at the Endoplasmic Reticulum and Relocates to the Plasma Membrane in Hypoxic Conditions Cells SUCNR1/GPR91 succinate GPCR N-glycosylation endoplasmic reticulum angiogenesis |
| title | The Succinate Receptor SUCNR1 Resides at the Endoplasmic Reticulum and Relocates to the Plasma Membrane in Hypoxic Conditions |
| title_full | The Succinate Receptor SUCNR1 Resides at the Endoplasmic Reticulum and Relocates to the Plasma Membrane in Hypoxic Conditions |
| title_fullStr | The Succinate Receptor SUCNR1 Resides at the Endoplasmic Reticulum and Relocates to the Plasma Membrane in Hypoxic Conditions |
| title_full_unstemmed | The Succinate Receptor SUCNR1 Resides at the Endoplasmic Reticulum and Relocates to the Plasma Membrane in Hypoxic Conditions |
| title_short | The Succinate Receptor SUCNR1 Resides at the Endoplasmic Reticulum and Relocates to the Plasma Membrane in Hypoxic Conditions |
| title_sort | succinate receptor sucnr1 resides at the endoplasmic reticulum and relocates to the plasma membrane in hypoxic conditions |
| topic | SUCNR1/GPR91 succinate GPCR N-glycosylation endoplasmic reticulum angiogenesis |
| url | https://www.mdpi.com/2073-4409/11/14/2185 |
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