Type 1 Cannabinoid Receptor Ligands Display Functional Selectivity in a Cell Culture Model of Striatal Medium Spiny Projection Neurons [Cell Biology]

July 18th, 2014 by Laprairie, R. B., Bagher, A. M., Kelly, M. E. M., Dupre, D. J., Denovan–Wright, E. M.

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), anandamide (AEA)], two synthetic cannabinoids (WIN55,212-2, 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/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 Gαi/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 Gαq-dependent pathways. CP55,940 and CBD both signaled through Gαs. CP, but not CBD, activated downstream Gαs pathways via CB1 targets. THC and CP55,940 promoted CB1 internalization and decreased CB1 protein levels over 18 h. These data demonstrate that individual cannabinoids display functional selectivity at CB1 leading to activation of distinct signaling pathways. In order to effectively match cannabinoids with therapeutic goals, these compounds must be screened for their signaling bias.
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