α1-adrenoceptor ligands inhibit chemokine receptor heteromerization partners of α1B/D-adrenoceptors via interference with heteromer formation
We reported previously that α1-adrenoceptor (α1-AR) ligands inhibit chemokine receptor (CR) heteromerization partners of α1B/D-AR. The underlying mechanisms are unknown and in vivo evidence for such effects is missing. Utilizing CCR2 and α1B-AR as prototypical partners, we observed in recombinant sy...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-04-01
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| Series: | Pharmacological Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1043661823000865 |
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| author | Xianlong Gao Garrett A. Enten Michelle Y. McGee McWayne Weche Matthias Majetschak |
| author_facet | Xianlong Gao Garrett A. Enten Michelle Y. McGee McWayne Weche Matthias Majetschak |
| author_sort | Xianlong Gao |
| collection | DOAJ |
| description | We reported previously that α1-adrenoceptor (α1-AR) ligands inhibit chemokine receptor (CR) heteromerization partners of α1B/D-AR. The underlying mechanisms are unknown and in vivo evidence for such effects is missing. Utilizing CCR2 and α1B-AR as prototypical partners, we observed in recombinant systems and THP-1 cells that α1B-AR enhanced whereas its absence inhibited Gαi signaling of CCR2. Phenylephrine and phentolamine reduced the CCR2:α1B-AR heteromerization propensity and inhibited Gαi signaling of CCR2. Phenylephrine cross-recruited β-arrestin-2 to CCR2, and reduced expression of α1B/D-AR, CR partners (CCR1/2, CXCR4) and corresponding heteromers. Phentolamine reduced CR:α1B/D-AR heteromers without affecting β-arrestin-2 recruitment or receptor expression. Phenylephrine/phentolamine prevented leukocyte infiltration mediated via CR heteromerization partners in a murine air pouch model. Our findings document that α1-AR ligands inhibit leukocyte migration mediated by CR heteromerization partners in vivo and suggest interference with α1B-AR:CR heteromerization as a mechanism by which CR partners are inhibited. These findings provide new insights into the pharmacology of GPCR heteromers and indicate that an agonist and antagonist at one GPCR can act as antagonists at heteromerization partners of their target receptors. |
| first_indexed | 2024-03-09T14:05:53Z |
| format | Article |
| id | doaj.art-6b8bec8df6bc403c88e6d0b85bc1297a |
| institution | Directory Open Access Journal |
| issn | 1096-1186 |
| language | English |
| last_indexed | 2024-03-09T14:05:53Z |
| publishDate | 2023-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Pharmacological Research |
| spelling | doaj.art-6b8bec8df6bc403c88e6d0b85bc1297a2023-11-30T05:05:59ZengElsevierPharmacological Research1096-11862023-04-01190106730α1-adrenoceptor ligands inhibit chemokine receptor heteromerization partners of α1B/D-adrenoceptors via interference with heteromer formationXianlong Gao0Garrett A. Enten1Michelle Y. McGee2McWayne Weche3Matthias Majetschak4Department of Surgery, Morsani College of Medicine, University of South Florida, Tampa, FL, USADepartment of Surgery, Morsani College of Medicine, University of South Florida, Tampa, FL, USA; Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL, USADepartment of Surgery, Morsani College of Medicine, University of South Florida, Tampa, FL, USADepartment of Surgery, Morsani College of Medicine, University of South Florida, Tampa, FL, USADepartment of Surgery, Morsani College of Medicine, University of South Florida, Tampa, FL, USA; Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL, USA; Correspondence to: University of South Florida, 12901 Bruce B Downs Blvd., MDC 3127, Tampa, FL 33612, USA.We reported previously that α1-adrenoceptor (α1-AR) ligands inhibit chemokine receptor (CR) heteromerization partners of α1B/D-AR. The underlying mechanisms are unknown and in vivo evidence for such effects is missing. Utilizing CCR2 and α1B-AR as prototypical partners, we observed in recombinant systems and THP-1 cells that α1B-AR enhanced whereas its absence inhibited Gαi signaling of CCR2. Phenylephrine and phentolamine reduced the CCR2:α1B-AR heteromerization propensity and inhibited Gαi signaling of CCR2. Phenylephrine cross-recruited β-arrestin-2 to CCR2, and reduced expression of α1B/D-AR, CR partners (CCR1/2, CXCR4) and corresponding heteromers. Phentolamine reduced CR:α1B/D-AR heteromers without affecting β-arrestin-2 recruitment or receptor expression. Phenylephrine/phentolamine prevented leukocyte infiltration mediated via CR heteromerization partners in a murine air pouch model. Our findings document that α1-AR ligands inhibit leukocyte migration mediated by CR heteromerization partners in vivo and suggest interference with α1B-AR:CR heteromerization as a mechanism by which CR partners are inhibited. These findings provide new insights into the pharmacology of GPCR heteromers and indicate that an agonist and antagonist at one GPCR can act as antagonists at heteromerization partners of their target receptors.http://www.sciencedirect.com/science/article/pii/S1043661823000865G protein coupled receptor heteromersGαi couplingβ-arrestin-2CAMPReceptor internalizationBioluminescence resonance energy transfer |
| spellingShingle | Xianlong Gao Garrett A. Enten Michelle Y. McGee McWayne Weche Matthias Majetschak α1-adrenoceptor ligands inhibit chemokine receptor heteromerization partners of α1B/D-adrenoceptors via interference with heteromer formation Pharmacological Research G protein coupled receptor heteromers Gαi coupling β-arrestin-2 CAMP Receptor internalization Bioluminescence resonance energy transfer |
| title | α1-adrenoceptor ligands inhibit chemokine receptor heteromerization partners of α1B/D-adrenoceptors via interference with heteromer formation |
| title_full | α1-adrenoceptor ligands inhibit chemokine receptor heteromerization partners of α1B/D-adrenoceptors via interference with heteromer formation |
| title_fullStr | α1-adrenoceptor ligands inhibit chemokine receptor heteromerization partners of α1B/D-adrenoceptors via interference with heteromer formation |
| title_full_unstemmed | α1-adrenoceptor ligands inhibit chemokine receptor heteromerization partners of α1B/D-adrenoceptors via interference with heteromer formation |
| title_short | α1-adrenoceptor ligands inhibit chemokine receptor heteromerization partners of α1B/D-adrenoceptors via interference with heteromer formation |
| title_sort | α1 adrenoceptor ligands inhibit chemokine receptor heteromerization partners of α1b d adrenoceptors via interference with heteromer formation |
| topic | G protein coupled receptor heteromers Gαi coupling β-arrestin-2 CAMP Receptor internalization Bioluminescence resonance energy transfer |
| url | http://www.sciencedirect.com/science/article/pii/S1043661823000865 |
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