Premium
Different classes of CB 1 ligands bias CB 1 ‐dependent signal transduction
Author(s) -
Laprairie Robert Brad,
Dupre Denis J,
Kelly Melanie EM,
DenovanWright Eileen M
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.lb553
Subject(s) - functional selectivity , signal transduction , cannabinoid receptor , anandamide , pharmacology , cannabinoid , endocannabinoid system , chemistry , receptor , intrinsic activity , cannabinoid receptor agonists , agonist , neuroscience , g protein coupled receptor , biology , biochemistry
Biased agonism describes the ligand‐dependent selectivity of different signal transduction pathways by molecules that act as agonists at the same receptor. This functional selectivity may be exploited to alter the balance between signaling pathways downstream of a receptor. Agonists of the type 1 cannabinoid receptor (CB 1 ) are structurally diverse and include the aminoalkylindole WIN55,212–2, the endocannabinoid N‐ arachidonoyl ethanolamine (anadamide), and the Δ 9 ‐tetrahydrocannabinol (THC)‐like, CP55,940. Given the differences in potency and efficacy of these agonists, we sought to determine whether activation of CB 1 by these ligands resulted in biased signal transduction in a cell culture model of striatal neurons. We found that the THC‐like compound CP55,940 enhanced the interaction between CB 1 and β‐arrestin2 compared to vehicle, anandamide, and WIN55,212–2, which resulted in CB 1 internalization and persistent pERK signalling. In contrast, the endocannaibnoid anandamide and the aminoalkylindole WIN55,212–2 enhanced the interaction between CB 1 and G αi , and promoted a rapid and transient increase in pERK signaling compared to vehicle or CP55,940. Based on these data, the therapeutic efficacy of cannabinoid agonists may be maximized by selecting agents with specific potency, affinity, and signaling bias.