Type 1 cannabinoid receptor ligands display functional selectivity in a cell culture model of striatal medium spiny projection neurons

Résultat de recherche: Articleexamen par les pairs

121 Citations (Scopus)

Résumé

Modulation of type 1 cannabinoid receptor (CB1) activity has been touted as a potential means of treating addiction, anxiety, depression, and neurodegeneration. Different agonists of CB1are known to evoke varied responses in vivo. Functional selectivity is the ligand-specific activation of certain signal transduction pathways at a receptor that can signal through multiple pathways.Tounderstand cannabinoid-specific functional selectivity, different groups have examined the effect of individual cannabinoids on various signaling pathways in heterologous expression systems. In the current study, we compared the functional selectivity of six cannabinoids, including two endocannabinoids (2-arachidonyl glycerol (2-AG) and anandamide (AEA)), two synthetic cannabinoids (WIN55,212-2 and CP55,940), and two phytocannabinoids (cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC)) on arrestin2-, Gαi/o-, Gβγ-, Gαs-, and Gαq-mediated intracellular signaling in the mouse STHdhQ7/Q7cell culture model of striatal medium spiny projection neurons that endogenously express CB1. In this system, 2-AG, THC, and CP55,940 were more potent mediators of arrestin2 recruitment than other cannabinoids tested. 2-AG, AEA, and WIN55,212-2, enhanced Gαi/oand Gβγ signaling, with 2-AG and AEA treatment leading to increased total CB1levels. 2-AG, AEA, THC, and WIN55,212-2 also activated Gαq-dependent pathways. CP55,940 and CBD both signaled through Gαs. CP55,940, but not CBD, activated downstream Gαspathways via CB1targets. THC and CP55,940 promoted CB1internalization and decreased CB1protein levels over an 18-h period. These data demonstrate that individual cannabinoids display functional selectivity at CB1leading to activation of distinct signaling pathways. To effectively match cannabinoids with therapeutic goals, these compounds must be screened for their signaling bias.

Langue d'origineEnglish
Pages (de-à)24845-24862
Nombre de pages18
JournalJournal of Biological Chemistry
Volume289
Numéro de publication36
DOI
Statut de publicationPublished - 2014

Note bibliographique

Publisher Copyright:
© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

ASJC Scopus Subject Areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't

Empreinte numérique

Plonger dans les sujets de recherche 'Type 1 cannabinoid receptor ligands display functional selectivity in a cell culture model of striatal medium spiny projection neurons'. Ensemble, ils forment une empreinte numérique unique.

Citer

Laprairie, R. B., Bagher, A. M., Kelly, M. E. M., Dupré, D. J., & Denovan-Wright, E. M. (2014). Type 1 cannabinoid receptor ligands display functional selectivity in a cell culture model of striatal medium spiny projection neurons. Journal of Biological Chemistry, 289(36), 24845-24862. https://doi.org/10.1074/jbc.M114.557025