Indomethacin Enhances Type 1 Cannabinoid Receptor Signaling
In addition to its known actions as a non-selective cyclooxygenase (COX) 1 and 2 inhibitor, we hypothesized that indomethacin can act as an allosteric modulator of the type 1 cannabinoid receptor (CB1R) because of its shared structural features with the known allosteric modulators of CB1R. Indometha...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-10-01
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| Series: | Frontiers in Molecular Neuroscience |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fnmol.2019.00257/full |
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| author | Robert B. Laprairie Robert B. Laprairie Kawthar A. Mohamed Ayat Zagzoog Melanie E. M. Kelly Melanie E. M. Kelly Lesley A. Stevenson Roger Pertwee Eileen M. Denovan-Wright Ganesh A. Thakur |
| author_facet | Robert B. Laprairie Robert B. Laprairie Kawthar A. Mohamed Ayat Zagzoog Melanie E. M. Kelly Melanie E. M. Kelly Lesley A. Stevenson Roger Pertwee Eileen M. Denovan-Wright Ganesh A. Thakur |
| author_sort | Robert B. Laprairie |
| collection | DOAJ |
| description | In addition to its known actions as a non-selective cyclooxygenase (COX) 1 and 2 inhibitor, we hypothesized that indomethacin can act as an allosteric modulator of the type 1 cannabinoid receptor (CB1R) because of its shared structural features with the known allosteric modulators of CB1R. Indomethacin enhanced the binding of [3H]CP55940 to hCB1R and enhanced AEA-dependent [35S]GTPγS binding to hCB1R in Chinese hamster ovary (CHO) cell membranes. Indomethacin (1 μM) also enhanced CP55940-dependent βarrestin1 recruitment, cAMP inhibition, ERK1/2 and PLCβ3 phosphorylation in HEK293A cells expressing hCB1R, but not in cells expressing hCB2R. Finally, indomethacin enhanced the magnitude and duration of CP55940-induced hypolocomotion, immobility, hypothermia, and anti-nociception in C57BL/6J mice. Together, these data support the hypothesis that indomethacin acted as a positive allosteric modulator of hCB1R. The identification of structural and functional features shared amongst allosteric modulators of CB1R may lead to the development of novel compounds designed for greater CB1R or COX selectivity and compounds designed to modulate both the prostaglandin and endocannabinoid systems. |
| first_indexed | 2024-12-22T14:58:15Z |
| format | Article |
| id | doaj.art-0af22acc2b2c405fb3735e48f6927486 |
| institution | Directory Open Access Journal |
| issn | 1662-5099 |
| language | English |
| last_indexed | 2024-12-22T14:58:15Z |
| publishDate | 2019-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-0af22acc2b2c405fb3735e48f69274862022-12-21T18:22:10ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992019-10-011210.3389/fnmol.2019.00257482384Indomethacin Enhances Type 1 Cannabinoid Receptor SignalingRobert B. Laprairie0Robert B. Laprairie1Kawthar A. Mohamed2Ayat Zagzoog3Melanie E. M. Kelly4Melanie E. M. Kelly5Lesley A. Stevenson6Roger Pertwee7Eileen M. Denovan-Wright8Ganesh A. Thakur9College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK, CanadaDepartment of Pharmacology, Dalhousie University, Halifax, NS, CanadaCollege of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK, CanadaCollege of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK, CanadaDepartment of Pharmacology, Dalhousie University, Halifax, NS, CanadaDepartment of Ophthalmology and Visual Sciences, Dalhousie University, Halifax, NS, CanadaSchool of Medical Sciences, The Institute of Medical Sciences, University of Aberdeen, Aberdeen, United KingdomSchool of Medical Sciences, The Institute of Medical Sciences, University of Aberdeen, Aberdeen, United KingdomDepartment of Pharmacology, Dalhousie University, Halifax, NS, CanadaCenter for Drug Discovery, Department of Pharmaceutical Sciences, School of Pharmacy, Bouvé College of Health Sciences, Northeastern University, Boston, MA, United StatesIn addition to its known actions as a non-selective cyclooxygenase (COX) 1 and 2 inhibitor, we hypothesized that indomethacin can act as an allosteric modulator of the type 1 cannabinoid receptor (CB1R) because of its shared structural features with the known allosteric modulators of CB1R. Indomethacin enhanced the binding of [3H]CP55940 to hCB1R and enhanced AEA-dependent [35S]GTPγS binding to hCB1R in Chinese hamster ovary (CHO) cell membranes. Indomethacin (1 μM) also enhanced CP55940-dependent βarrestin1 recruitment, cAMP inhibition, ERK1/2 and PLCβ3 phosphorylation in HEK293A cells expressing hCB1R, but not in cells expressing hCB2R. Finally, indomethacin enhanced the magnitude and duration of CP55940-induced hypolocomotion, immobility, hypothermia, and anti-nociception in C57BL/6J mice. Together, these data support the hypothesis that indomethacin acted as a positive allosteric modulator of hCB1R. The identification of structural and functional features shared amongst allosteric modulators of CB1R may lead to the development of novel compounds designed for greater CB1R or COX selectivity and compounds designed to modulate both the prostaglandin and endocannabinoid systems.https://www.frontiersin.org/article/10.3389/fnmol.2019.00257/fullcannabinoidindomethacincannabinoid receptorallosteric modulatormolecular pharmacologycell signaling |
| spellingShingle | Robert B. Laprairie Robert B. Laprairie Kawthar A. Mohamed Ayat Zagzoog Melanie E. M. Kelly Melanie E. M. Kelly Lesley A. Stevenson Roger Pertwee Eileen M. Denovan-Wright Ganesh A. Thakur Indomethacin Enhances Type 1 Cannabinoid Receptor Signaling Frontiers in Molecular Neuroscience cannabinoid indomethacin cannabinoid receptor allosteric modulator molecular pharmacology cell signaling |
| title | Indomethacin Enhances Type 1 Cannabinoid Receptor Signaling |
| title_full | Indomethacin Enhances Type 1 Cannabinoid Receptor Signaling |
| title_fullStr | Indomethacin Enhances Type 1 Cannabinoid Receptor Signaling |
| title_full_unstemmed | Indomethacin Enhances Type 1 Cannabinoid Receptor Signaling |
| title_short | Indomethacin Enhances Type 1 Cannabinoid Receptor Signaling |
| title_sort | indomethacin enhances type 1 cannabinoid receptor signaling |
| topic | cannabinoid indomethacin cannabinoid receptor allosteric modulator molecular pharmacology cell signaling |
| url | https://www.frontiersin.org/article/10.3389/fnmol.2019.00257/full |
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