Cannabinoid CB1 and CB2 Receptor Signaling and Bias

Abstract

An agonist that acts through a single receptor can activate numerous signaling pathways. Recent studies have suggested that different ligands can differentially activate these pathways by stabilizing a limited range of receptor conformations, which in turn preferentially drive different downstream signaling cascades. This concept, termed "biased signaling" represents an exciting therapeutic opportunity to target specific pathways that elicit only desired effects, while avoiding undesired effects mediated by different signaling cascades. The cannabinoid receptors CB₁ and CB₂ each activate multiple pathways, and evidence is emerging for bias within these pathways. This review will summarize the current evidence for biased signaling through cannabinoid receptor subtypes CB₁ and CB₂.

Keywords: G protein-coupled receptor; agonist bias; cannabinoid receptors; functional selectivity.

FIG. 1.

Biased agonist 1 or 2 binds to the seven-transmembrane cannabinoid receptor 1. Structurally different ligands will induce diverse conformations of the receptor, which may then favor one of the possible signaling pathways over others. In this diagram, agonist 1 is biased toward the activation of the Gα_i/o heterotrimer over β-arrestin-1, while agonist 2 favorably activates β-arrestin-1. Activation of Gα_i/o prompts the release of the Gβγ subunit, which inhibits voltage-dependent calcium channels (I_Ca) and activates GIRK. The Gα_i/o subunit inhibits AC, which stimulates the phosphorylation and early activation of ERK1/2. The activation of β-arrestin-1 conversely induces late activation of ERK1/2. AC, adenylyl cyclase; ERK1/2, extracellular signal-regulated kinase 1 or 2; GIRK, G protein-gated inwardly rectifying potassium channels.