Differential effects of glucose‐dependent insulinotropic polypeptide receptor/glucagon‐like peptide‐1 receptor heteromerization on cell signaling when expressed in HEK‐293 cells
Abstract The incretin hormones: glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) are important regulators of many aspects of metabolism including insulin secretion. Their receptors (GIPR and GLP‐1R) are closely related members of the secretin class of G‐protein‐...
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| Format: | Article |
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Wiley
2022-10-01
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| Series: | Pharmacology Research & Perspectives |
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| Online Access: | https://doi.org/10.1002/prp2.1013 |
| _version_ | 1817984763503312896 |
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| author | Bashaier Al‐Zaid Siby Chacko Charles Ifeamalume Ezeamuzie Moritz Bünemann Cornelius Krasel Tina Karimian Peter Lanzerstorfer Suleiman Al‐Sabah |
| author_facet | Bashaier Al‐Zaid Siby Chacko Charles Ifeamalume Ezeamuzie Moritz Bünemann Cornelius Krasel Tina Karimian Peter Lanzerstorfer Suleiman Al‐Sabah |
| author_sort | Bashaier Al‐Zaid |
| collection | DOAJ |
| description | Abstract The incretin hormones: glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) are important regulators of many aspects of metabolism including insulin secretion. Their receptors (GIPR and GLP‐1R) are closely related members of the secretin class of G‐protein‐coupled receptors. As both receptors are expressed on pancreatic β‐cells there is at least the hypothetical possibility that they may form heteromers. In the present study, we investigated GIPR/GLP‐1R heteromerization and the impact of GIPR on GLP‐1R‐mediated signaling and vice versa in HEK‐293 cells. Real‐time fluorescence resonance energy transfer (FRET) and bioluminescence resonance energy transfer (BRET) saturation experiments confirm that GLP‐1R and GIPR form heteromers. Stimulation with 1 μM GLP‐1 caused an increase in both FRET and BRET ratio, whereas stimulation with 1 μM GIP caused a decrease. The only other ligand tested to cause a significant change in BRET signal was the GLP‐1 metabolite, GLP‐1 (9–36). GIPR expression had no significant effect on mini‐Gs recruitment to GLP‐1R but significantly inhibited GLP‐1 stimulated mini‐Gq and arrestin recruitment. In contrast, the presence of GLP‐1R improved GIP stimulated mini‐Gs and mini‐Gq recruitment to GIPR. These data support the hypothesis that GIPR and GLP‐1R form heteromers with differential consequences on cell signaling. |
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| format | Article |
| id | doaj.art-6e922dfe4b3046d1b2fd74ffc8831fbc |
| institution | Directory Open Access Journal |
| issn | 2052-1707 |
| language | English |
| last_indexed | 2024-04-13T23:49:01Z |
| publishDate | 2022-10-01 |
| publisher | Wiley |
| record_format | Article |
| series | Pharmacology Research & Perspectives |
| spelling | doaj.art-6e922dfe4b3046d1b2fd74ffc8831fbc2022-12-22T02:24:11ZengWileyPharmacology Research & Perspectives2052-17072022-10-01105n/an/a10.1002/prp2.1013Differential effects of glucose‐dependent insulinotropic polypeptide receptor/glucagon‐like peptide‐1 receptor heteromerization on cell signaling when expressed in HEK‐293 cellsBashaier Al‐Zaid0Siby Chacko1Charles Ifeamalume Ezeamuzie2Moritz Bünemann3Cornelius Krasel4Tina Karimian5Peter Lanzerstorfer6Suleiman Al‐Sabah7Department of Pharmacology and Toxicology, Faculty of Medicine Kuwait University Kuwait City KuwaitDepartment of Pharmacology and Toxicology, Faculty of Medicine Kuwait University Kuwait City KuwaitDepartment of Pharmacology and Toxicology, Faculty of Medicine Kuwait University Kuwait City KuwaitSchool of Pharmacy, Institute for Pharmacology and Toxicology The Philipps University of Marburg Marburg GermanySchool of Pharmacy, Institute for Pharmacology and Toxicology The Philipps University of Marburg Marburg GermanyUniversity of Applied Sciences Upper Austria, School of Engineering Wels AustriaUniversity of Applied Sciences Upper Austria, School of Engineering Wels AustriaDepartment of Pharmacology and Toxicology, Faculty of Medicine Kuwait University Kuwait City KuwaitAbstract The incretin hormones: glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) are important regulators of many aspects of metabolism including insulin secretion. Their receptors (GIPR and GLP‐1R) are closely related members of the secretin class of G‐protein‐coupled receptors. As both receptors are expressed on pancreatic β‐cells there is at least the hypothetical possibility that they may form heteromers. In the present study, we investigated GIPR/GLP‐1R heteromerization and the impact of GIPR on GLP‐1R‐mediated signaling and vice versa in HEK‐293 cells. Real‐time fluorescence resonance energy transfer (FRET) and bioluminescence resonance energy transfer (BRET) saturation experiments confirm that GLP‐1R and GIPR form heteromers. Stimulation with 1 μM GLP‐1 caused an increase in both FRET and BRET ratio, whereas stimulation with 1 μM GIP caused a decrease. The only other ligand tested to cause a significant change in BRET signal was the GLP‐1 metabolite, GLP‐1 (9–36). GIPR expression had no significant effect on mini‐Gs recruitment to GLP‐1R but significantly inhibited GLP‐1 stimulated mini‐Gq and arrestin recruitment. In contrast, the presence of GLP‐1R improved GIP stimulated mini‐Gs and mini‐Gq recruitment to GIPR. These data support the hypothesis that GIPR and GLP‐1R form heteromers with differential consequences on cell signaling.https://doi.org/10.1002/prp2.1013BRET4FRET3G‐protein‐coupled receptor1GIP6GLP‐15heteromerization2 |
| spellingShingle | Bashaier Al‐Zaid Siby Chacko Charles Ifeamalume Ezeamuzie Moritz Bünemann Cornelius Krasel Tina Karimian Peter Lanzerstorfer Suleiman Al‐Sabah Differential effects of glucose‐dependent insulinotropic polypeptide receptor/glucagon‐like peptide‐1 receptor heteromerization on cell signaling when expressed in HEK‐293 cells Pharmacology Research & Perspectives BRET4 FRET3 G‐protein‐coupled receptor1 GIP6 GLP‐15 heteromerization2 |
| title | Differential effects of glucose‐dependent insulinotropic polypeptide receptor/glucagon‐like peptide‐1 receptor heteromerization on cell signaling when expressed in HEK‐293 cells |
| title_full | Differential effects of glucose‐dependent insulinotropic polypeptide receptor/glucagon‐like peptide‐1 receptor heteromerization on cell signaling when expressed in HEK‐293 cells |
| title_fullStr | Differential effects of glucose‐dependent insulinotropic polypeptide receptor/glucagon‐like peptide‐1 receptor heteromerization on cell signaling when expressed in HEK‐293 cells |
| title_full_unstemmed | Differential effects of glucose‐dependent insulinotropic polypeptide receptor/glucagon‐like peptide‐1 receptor heteromerization on cell signaling when expressed in HEK‐293 cells |
| title_short | Differential effects of glucose‐dependent insulinotropic polypeptide receptor/glucagon‐like peptide‐1 receptor heteromerization on cell signaling when expressed in HEK‐293 cells |
| title_sort | differential effects of glucose dependent insulinotropic polypeptide receptor glucagon like peptide 1 receptor heteromerization on cell signaling when expressed in hek 293 cells |
| topic | BRET4 FRET3 G‐protein‐coupled receptor1 GIP6 GLP‐15 heteromerization2 |
| url | https://doi.org/10.1002/prp2.1013 |
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