Indomethacin Enhances Type 1 Cannabinoid Receptor Signaling

Robert B. Laprairie; Kawthar A. Mohamed; Ayat Zagzoog; Melanie E.M. Kelly; Lesley A. Stevenson; Roger Pertwee; Eileen M. Denovan-Wright; Ganesh A. Thakur

doi:10.3389/fnmol.2019.00257

Indomethacin Enhances Type 1 Cannabinoid Receptor Signaling

Robert B. Laprairie, Kawthar A. Mohamed, Ayat Zagzoog, Melanie E.M. Kelly, Lesley A. Stevenson, Roger Pertwee, Eileen M. Denovan-Wright, Ganesh A. Thakur

Medicine

Medicine

Résultat de recherche: Article › examen par les pairs

10 Citations (Scopus)

Résumé

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.

Langue d'origine	English
Numéro d'article	257
Journal	Frontiers in Molecular Neuroscience
Volume	12
DOI	https://doi.org/10.3389/fnmol.2019.00257
Statut de publication	Published - oct. 18 2019

Note bibliographique

Funding Information:
We thank Dr. Alex Straiker for his independent review of the data. We thank Dr. Amina Bagher for her assistance in blinding and conducting animal experiments. Funding. KM is supported by a scholarship from the Natural Sciences and Engineering Research Council (NSERC USRA). This work was supported by grants from the National Institutes on Drug Abuse (NIDA) at the National Institutes of Health (NIH) to RP, MK, and GT (DA027113 and EY024717); a Bridge Funding Grant from Dalhousie University to ED-W; and a partnership grant from GlaxoSmithKline-Canadian Institutes of Health Research (CIHR, 368247) and a Collaborative Research and Development grant (NSERC, CRDPJ 517839-17) to RL.

Funding Information:
KM is supported by a scholarship from the Natural Sciences and Engineering Research Council (NSERC USRA). This work was supported by grants from the National Institutes on Drug Abuse (NIDA) at the National Institutes of Health (NIH) to RP, MK, and GT (DA027113 and EY024717); a Bridge Funding Grant from Dalhousie University to ED-W; and a partnership grant from GlaxoSmithKline-Canadian Institutes of Health Research (CIHR, 368247) and a Collaborative Research and Development grant (NSERC, CRDPJ 517839-17) to RL.

Publisher Copyright:
© Copyright © 2019 Laprairie, Mohamed, Zagzoog, Kelly, Stevenson, Pertwee, Denovan-Wright and Thakur.

ASJC Scopus Subject Areas

Molecular Biology
Cellular and Molecular Neuroscience

Accès au document

10.3389/fnmol.2019.00257

Autres fichiers et liens

Citer

@article{2dde8de6510c4e27abcf0e95398c6cf9,

title = "Indomethacin Enhances Type 1 Cannabinoid Receptor Signaling",

abstract = "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.",

author = "Laprairie, {Robert B.} and Mohamed, {Kawthar A.} and Ayat Zagzoog and Kelly, {Melanie E.M.} and Stevenson, {Lesley A.} and Roger Pertwee and Denovan-Wright, {Eileen M.} and Thakur, {Ganesh A.}",

note = "Funding Information: We thank Dr. Alex Straiker for his independent review of the data. We thank Dr. Amina Bagher for her assistance in blinding and conducting animal experiments. Funding. KM is supported by a scholarship from the Natural Sciences and Engineering Research Council (NSERC USRA). This work was supported by grants from the National Institutes on Drug Abuse (NIDA) at the National Institutes of Health (NIH) to RP, MK, and GT (DA027113 and EY024717); a Bridge Funding Grant from Dalhousie University to ED-W; and a partnership grant from GlaxoSmithKline-Canadian Institutes of Health Research (CIHR, 368247) and a Collaborative Research and Development grant (NSERC, CRDPJ 517839-17) to RL. Funding Information: KM is supported by a scholarship from the Natural Sciences and Engineering Research Council (NSERC USRA). This work was supported by grants from the National Institutes on Drug Abuse (NIDA) at the National Institutes of Health (NIH) to RP, MK, and GT (DA027113 and EY024717); a Bridge Funding Grant from Dalhousie University to ED-W; and a partnership grant from GlaxoSmithKline-Canadian Institutes of Health Research (CIHR, 368247) and a Collaborative Research and Development grant (NSERC, CRDPJ 517839-17) to RL. Publisher Copyright: {\textcopyright} Copyright {\textcopyright} 2019 Laprairie, Mohamed, Zagzoog, Kelly, Stevenson, Pertwee, Denovan-Wright and Thakur.",

year = "2019",

month = oct,

day = "18",

doi = "10.3389/fnmol.2019.00257",

language = "English",

volume = "12",

journal = "Frontiers in Molecular Neuroscience",

issn = "1662-5099",

publisher = "Frontiers Research Foundation",

}

TY - JOUR

T1 - Indomethacin Enhances Type 1 Cannabinoid Receptor Signaling

AU - Laprairie, Robert B.

AU - Mohamed, Kawthar A.

AU - Zagzoog, Ayat

AU - Kelly, Melanie E.M.

AU - Stevenson, Lesley A.

AU - Pertwee, Roger

AU - Denovan-Wright, Eileen M.

AU - Thakur, Ganesh A.

N1 - Funding Information: We thank Dr. Alex Straiker for his independent review of the data. We thank Dr. Amina Bagher for her assistance in blinding and conducting animal experiments. Funding. KM is supported by a scholarship from the Natural Sciences and Engineering Research Council (NSERC USRA). This work was supported by grants from the National Institutes on Drug Abuse (NIDA) at the National Institutes of Health (NIH) to RP, MK, and GT (DA027113 and EY024717); a Bridge Funding Grant from Dalhousie University to ED-W; and a partnership grant from GlaxoSmithKline-Canadian Institutes of Health Research (CIHR, 368247) and a Collaborative Research and Development grant (NSERC, CRDPJ 517839-17) to RL. Funding Information: KM is supported by a scholarship from the Natural Sciences and Engineering Research Council (NSERC USRA). This work was supported by grants from the National Institutes on Drug Abuse (NIDA) at the National Institutes of Health (NIH) to RP, MK, and GT (DA027113 and EY024717); a Bridge Funding Grant from Dalhousie University to ED-W; and a partnership grant from GlaxoSmithKline-Canadian Institutes of Health Research (CIHR, 368247) and a Collaborative Research and Development grant (NSERC, CRDPJ 517839-17) to RL. Publisher Copyright: © Copyright © 2019 Laprairie, Mohamed, Zagzoog, Kelly, Stevenson, Pertwee, Denovan-Wright and Thakur.

PY - 2019/10/18

Y1 - 2019/10/18

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85074645528&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85074645528&partnerID=8YFLogxK

U2 - 10.3389/fnmol.2019.00257

DO - 10.3389/fnmol.2019.00257

M3 - Article

AN - SCOPUS:85074645528

SN - 1662-5099

VL - 12

JO - Frontiers in Molecular Neuroscience

JF - Frontiers in Molecular Neuroscience

M1 - 257

ER -

Indomethacin Enhances Type 1 Cannabinoid Receptor Signaling

Résumé

Note bibliographique

ASJC Scopus Subject Areas

Accès au document

Autres fichiers et liens

Empreinte numérique

Citer