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Type 1 cannabinoid receptor ligands display functional selectivity in a cell culture model of striatal medium spiny projection neurons.
J Biol Chem 2014; 289(36):24845-62JB

Abstract

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 CB1 are 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. To understand 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 Δ(9)-tetrahydrocannabinol (THC)) on arrestin2-, Gα(i/o)-, Gβγ-, Gα(s)-, and Gα(q)-mediated intracellular signaling in the mouse STHdh(Q7/Q7) cell 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 Gα(i/o) and Gβγ signaling, with 2-AG and AEA treatment leading to increased total CB1 levels. 2-AG, AEA, THC, and WIN55,212-2 also activated Gα(q)-dependent pathways. CP55,940 and CBD both signaled through Gα(s). CP55,940, but not CBD, activated downstream Gα(s) pathways via CB1 targets. THC and CP55,940 promoted CB1 internalization and decreased CB1 protein levels over an 18-h period. These data demonstrate that individual cannabinoids display functional selectivity at CB1 leading to activation of distinct signaling pathways. To effectively match cannabinoids with therapeutic goals, these compounds must be screened for their signaling bias.

Authors+Show Affiliations

From the Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada.From the Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada.From the Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada.From the Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada.From the Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada emdenova@dal.ca.

Pub Type(s)

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

Language

eng

PubMed ID

25037227

Citation

Laprairie, Robert B., et al. "Type 1 Cannabinoid Receptor Ligands Display Functional Selectivity in a Cell Culture Model of Striatal Medium Spiny Projection Neurons." The Journal of Biological Chemistry, vol. 289, no. 36, 2014, pp. 24845-62.
Laprairie RB, Bagher AM, Kelly ME, et al. Type 1 cannabinoid receptor ligands display functional selectivity in a cell culture model of striatal medium spiny projection neurons. J Biol Chem. 2014;289(36):24845-62.
Laprairie, R. B., Bagher, A. M., Kelly, M. E., 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. The Journal of Biological Chemistry, 289(36), pp. 24845-62. doi:10.1074/jbc.M114.557025.
Laprairie RB, et al. Type 1 Cannabinoid Receptor Ligands Display Functional Selectivity in a Cell Culture Model of Striatal Medium Spiny Projection Neurons. J Biol Chem. 2014 Sep 5;289(36):24845-62. PubMed PMID: 25037227.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Type 1 cannabinoid receptor ligands display functional selectivity in a cell culture model of striatal medium spiny projection neurons. AU - Laprairie,Robert B, AU - Bagher,Amina M, AU - Kelly,Melanie E M, AU - Dupré,Denis J, AU - Denovan-Wright,Eileen M, Y1 - 2014/07/18/ PY - 2014/7/20/entrez PY - 2014/7/20/pubmed PY - 2015/1/30/medline KW - 2-Arachidonylglycerol KW - Anandamide (N-Arachidonoylethanolamine) (AEA) KW - Arrestin KW - Bioluminescence Resonance Energy Transfer (BRET) KW - Cannabidiol KW - Cannabinoid KW - Cannabinoid Receptor KW - Cell Signaling KW - Neurobiology KW - Δ9-tetrahydrocannabinol (THC) SP - 24845 EP - 62 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 289 IS - 36 N2 - 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 CB1 are 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. To understand 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 Δ(9)-tetrahydrocannabinol (THC)) on arrestin2-, Gα(i/o)-, Gβγ-, Gα(s)-, and Gα(q)-mediated intracellular signaling in the mouse STHdh(Q7/Q7) cell 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 Gα(i/o) and Gβγ signaling, with 2-AG and AEA treatment leading to increased total CB1 levels. 2-AG, AEA, THC, and WIN55,212-2 also activated Gα(q)-dependent pathways. CP55,940 and CBD both signaled through Gα(s). CP55,940, but not CBD, activated downstream Gα(s) pathways via CB1 targets. THC and CP55,940 promoted CB1 internalization and decreased CB1 protein levels over an 18-h period. These data demonstrate that individual cannabinoids display functional selectivity at CB1 leading to activation of distinct signaling pathways. To effectively match cannabinoids with therapeutic goals, these compounds must be screened for their signaling bias. SN - 1083-351X UR - https://www.unboundmedicine.com/medline/citation/25037227/Type_1_cannabinoid_receptor_ligands_display_functional_selectivity_in_a_cell_culture_model_of_striatal_medium_spiny_projection_neurons_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=25037227 DB - PRIME DP - Unbound Medicine ER -