Research updateFunctional selectivity at G-protein coupled receptors: Advancing cannabinoid receptors as drug targets
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Section snippets
Pharmacological and drug-discovery implications of functional selectivity
According to the tenets of the traditional “two-state” model of G protein-coupled receptor (GPCR) function, a GPCR acts as a ligand-controlled “on-off” switch, eliciting, when activated by an agonist, a cascade of cellular signals and effects through specific transducers such as G proteins without any particular directionality to the ensuing information output [1]. Based upon data from an array of biophysical and biochemical studies, this outmoded paradigm has been elaborated to a so-called
Receptor-mediated cannabinoid physiology
The endogenous cannabinoid (“endocannabinoid”) system includes two principal class-A GPCRs: cannabinoid receptor 1 (CB1R), predominantly expressed in the brain [25] and to a lesser extent in the periphery [26], and cannabinoid receptor 2 (CB2R), expressed mainly in immune cells and during inflammatory injury in the central nervous system (CNS) [27]. CB2R has 44% overall sequence identity with CB1R and shows comparatively greater interspecies heterogeneity. Some 25 years ago, identification and
Functional selectivity at CB1R
All endocannabinoid signaling lipids, including the principal, arachidonic acid-derived mediators found in mammals, anandamide (AEA) (4, Fig. 2) and 2-arachidonoylglycerol (2-AG) (5, Fig. 2), preferentially activate Gi/o G proteins at CB1R (Table 1). Certain structurally distinct cannabinergic ligands, upon binding to CB1R, can elicit the receptor’s differential interaction with Gi and/or Go G-protein subtypes. HU210 (6, Fig. 2) activates both Gi and Go proteins to maximal efficacy, whereas
Functional selectivity at CB2R
Reminiscent of CB1R, CB2R can be activated by cannabinergic agents that signal differentially through various intracellular information pathways in a ligand-dependent manner (Table 2). CB2R preferably interacts with Gi over Go, the latter not widely expressed in the peripheral tissues where CB2R expression is high. Furthermore, at CB2R, HU210 produces a maximal Gi response unlike AEA, which produces a partial response [56]. At CB2R, low concentrations of CP55940 inhibit adenylyl cyclase and
Structural basis for signaling bias at cannabinoid GPCRs
Exponential progress in atomic-level structure determination of membrane proteins in the last few years has enabled the crystal structures of some 30 unique GPCRs, and over 119 different GPCR structures have been solved [68]. These structures have improved our understanding of the GPCR conformational states associated with (especially orthosteric) ligand engagement as they pertain to various activity states. The large outward displacement of transmembrane helix (TMH) 6 and inward movement of
Pharmacotherapeutic implications of biased signaling at CBRs
As a component of its overall pharmacological profile, the ability of a GPCR-targeted therapeutic candidate to activate differentially specific intracellular effector pathways carries critical implications for drug discovery. For example, niacin acts therapeutically as an antilipolytic agent by activating GPR109A receptor-mediated G-protein signaling. However, it also activates the G protein-independent β-arrestin1 pathway responsible for cutaneous flushing and other adverse effects [86].
Future research directions
Although it is well established that most GPCR ligands may exhibit pluridimensional efficacies with respect to different signaling pathways, challenges remain in the study of CBR functional selectivity. Experimental nuances such as kinetics of response, response read-out bias, cell/tissue-specific variations, and the system-dependency of the observed pharmacological effects may influence the qualitative nature of biased signaling and its quantification [98]. Stereochemical [65] and
Note added in proof
While this publication was in press, a review of ligand bias at CB1R/CB2R in the context of the central nervous system was published [123]. A new, high-resolution crystal structure of a liganded CB1R construct bound to the drug taranabant has also appeared in the literature [124] that offers some additional orthosteric ligand-docking predictions as compared to the previously-reported [77] CB1R X-ray structure.
Conflict of interest
The authors declare no conflicts of interest regarding the subject of this paper.
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