A lipidated peptide derived from the C-terminal tail of the vasopressin 2 receptor shows promise as a new β-arrestin inhibitor
β-arrestins play pivotal roles in seven transmembrane receptor (7TMR) signalling and trafficking. To study their functional role in regulating specific receptor systems, current research relies mainly on genetic tools, as few pharmacological options are available. To address this issue, we designed...
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Elsevier
2025-02-01
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| Series: | Pharmacological Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1043661825000222 |
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| author | Rebecca L. Brouillette Christine E. Mona Michael Desgagné Malihe Hassanzedeh Émile Breault Frédérique Lussier Karine Belleville Jean-Michel Longpré Michel Grandbois Pierre-Luc Boudreault Élie Besserer-Offroy Philippe Sarret |
| author_facet | Rebecca L. Brouillette Christine E. Mona Michael Desgagné Malihe Hassanzedeh Émile Breault Frédérique Lussier Karine Belleville Jean-Michel Longpré Michel Grandbois Pierre-Luc Boudreault Élie Besserer-Offroy Philippe Sarret |
| author_sort | Rebecca L. Brouillette |
| collection | DOAJ |
| description | β-arrestins play pivotal roles in seven transmembrane receptor (7TMR) signalling and trafficking. To study their functional role in regulating specific receptor systems, current research relies mainly on genetic tools, as few pharmacological options are available. To address this issue, we designed and synthesised a novel lipidated phosphomimetic peptide inhibitor targeting β-arrestins, called ARIP, which was developed based on the C-terminal tail (A343-S371) of the vasopressin V2 receptor. As the V2R sequence has been shown to bind β-arrestins with high affinity, we added an N-terminal palmitate residue to allow membrane tethering and cell entry. Here, using BRET2-based biosensors, we demonstrated the ability of ARIP to inhibit agonist-induced β-arrestin recruitment on a series of 7TMRs that includes both stable and transient β-arrestin binders, with efficiencies that depend on receptor type. In addition, we showed that ARIP was unable to recruit β-arrestins to the cell membrane by itself, and that it did not interfere with G protein signalling. Molecular modelling studies also revealed that ARIP binds β-arrestins as does V2Rpp, the phosphorylated peptide derived from V2R, and that replacing the p-Ser and p-Thr residues of V2Rpp with Glu residues does not alter ARIP’s inhibitory activity on β-arrestin recruitment. Importantly, ARIP exerted an opioid-sparing effect in vivo, as intrathecal injection of ARIP potentiated morphine’s analgesic effect in the tail-flick test, consistent with previous findings of genetic inhibition of β-arrestins. ARIP therefore represents a promising pharmacological tool for investigating the fine-tuning roles of β-arrestins in 7TMR-driven pathophysiological processes. |
| format | Article |
| id | doaj-art-3605c1e2b8f24a65a93b83b6aaaebba3 |
| institution | Kabale University |
| issn | 1096-1186 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Pharmacological Research |
| spelling | doaj-art-3605c1e2b8f24a65a93b83b6aaaebba32025-02-08T04:59:47ZengElsevierPharmacological Research1096-11862025-02-01212107597A lipidated peptide derived from the C-terminal tail of the vasopressin 2 receptor shows promise as a new β-arrestin inhibitorRebecca L. Brouillette0Christine E. Mona1Michael Desgagné2Malihe Hassanzedeh3Émile Breault4Frédérique Lussier5Karine Belleville6Jean-Michel Longpré7Michel Grandbois8Pierre-Luc Boudreault9Élie Besserer-Offroy10Philippe Sarret11Department of Pharmacology-Physiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada; Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, QC, CanadaAhmanson Translational Theranostics Division, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, UCLA Health, Los Angeles, CA, USADepartment of Pharmacology-Physiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada; Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, QC, CanadaDepartment of Pharmacology-Physiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada; Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, QC, CanadaDepartment of Pharmacology-Physiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada; Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, QC, CanadaDepartment of Pharmacology-Physiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada; Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, QC, CanadaDepartment of Pharmacology-Physiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada; Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, QC, CanadaDepartment of Pharmacology-Physiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada; Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, QC, CanadaDepartment of Pharmacology-Physiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada; Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, QC, CanadaDepartment of Pharmacology-Physiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada; Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, QC, Canada; RECITAL International Partnership Lab, Université de Caen-Normandie, Caen, France & Université de Sherbrooke, Sherbrooke, QC, CanadaDepartment of Pharmacology-Physiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada; Université de Caen Normandie, INSERM U1086 – Anticipe, Normandie Université, Caen, France; Baclesse Comprehensive Cancer Center, UNICANCER, Caen, France; RECITAL International Partnership Lab, Université de Caen-Normandie, Caen, France & Université de Sherbrooke, Sherbrooke, QC, Canada; Correspondence to: Inserm U1086 – Anticipe, Baclesse Comprehensive Cancer Center, Université de Caen-Normandie, 3 avenue du Général Harris, 14076 Cedex 5, Caen, France.Department of Pharmacology-Physiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada; Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, QC, Canada; RECITAL International Partnership Lab, Université de Caen-Normandie, Caen, France & Université de Sherbrooke, Sherbrooke, QC, Canada; Correspondence to: Department of Pharmacology-Physiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 3001, 12th Avenue North, Sherbrooke, QC J1H 5N4, Canada.β-arrestins play pivotal roles in seven transmembrane receptor (7TMR) signalling and trafficking. To study their functional role in regulating specific receptor systems, current research relies mainly on genetic tools, as few pharmacological options are available. To address this issue, we designed and synthesised a novel lipidated phosphomimetic peptide inhibitor targeting β-arrestins, called ARIP, which was developed based on the C-terminal tail (A343-S371) of the vasopressin V2 receptor. As the V2R sequence has been shown to bind β-arrestins with high affinity, we added an N-terminal palmitate residue to allow membrane tethering and cell entry. Here, using BRET2-based biosensors, we demonstrated the ability of ARIP to inhibit agonist-induced β-arrestin recruitment on a series of 7TMRs that includes both stable and transient β-arrestin binders, with efficiencies that depend on receptor type. In addition, we showed that ARIP was unable to recruit β-arrestins to the cell membrane by itself, and that it did not interfere with G protein signalling. Molecular modelling studies also revealed that ARIP binds β-arrestins as does V2Rpp, the phosphorylated peptide derived from V2R, and that replacing the p-Ser and p-Thr residues of V2Rpp with Glu residues does not alter ARIP’s inhibitory activity on β-arrestin recruitment. Importantly, ARIP exerted an opioid-sparing effect in vivo, as intrathecal injection of ARIP potentiated morphine’s analgesic effect in the tail-flick test, consistent with previous findings of genetic inhibition of β-arrestins. ARIP therefore represents a promising pharmacological tool for investigating the fine-tuning roles of β-arrestins in 7TMR-driven pathophysiological processes.http://www.sciencedirect.com/science/article/pii/S1043661825000222β-arrestinvasopressin 2 receptor (V2R)G protein-coupled receptor (GPCR)lipopeptidepepducininhibitor |
| spellingShingle | Rebecca L. Brouillette Christine E. Mona Michael Desgagné Malihe Hassanzedeh Émile Breault Frédérique Lussier Karine Belleville Jean-Michel Longpré Michel Grandbois Pierre-Luc Boudreault Élie Besserer-Offroy Philippe Sarret A lipidated peptide derived from the C-terminal tail of the vasopressin 2 receptor shows promise as a new β-arrestin inhibitor Pharmacological Research β-arrestin vasopressin 2 receptor (V2R) G protein-coupled receptor (GPCR) lipopeptide pepducin inhibitor |
| title | A lipidated peptide derived from the C-terminal tail of the vasopressin 2 receptor shows promise as a new β-arrestin inhibitor |
| title_full | A lipidated peptide derived from the C-terminal tail of the vasopressin 2 receptor shows promise as a new β-arrestin inhibitor |
| title_fullStr | A lipidated peptide derived from the C-terminal tail of the vasopressin 2 receptor shows promise as a new β-arrestin inhibitor |
| title_full_unstemmed | A lipidated peptide derived from the C-terminal tail of the vasopressin 2 receptor shows promise as a new β-arrestin inhibitor |
| title_short | A lipidated peptide derived from the C-terminal tail of the vasopressin 2 receptor shows promise as a new β-arrestin inhibitor |
| title_sort | lipidated peptide derived from the c terminal tail of the vasopressin 2 receptor shows promise as a new β arrestin inhibitor |
| topic | β-arrestin vasopressin 2 receptor (V2R) G protein-coupled receptor (GPCR) lipopeptide pepducin inhibitor |
| url | http://www.sciencedirect.com/science/article/pii/S1043661825000222 |
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