Efficacy in CB1 receptor-mediated signal transduction

Abstract

CB(1) receptor cellular signal transduction is dependent on the expression of G proteins to which the receptor couples, the potential for precoupling of particular G proteins to the receptors either by scaffolding mechanisms or colocalization in lipid raft domains, and the effector mechanisms that these transducer molecules regulate. This discourse will evaluate studies of efficacy for CB(1) receptor-Gi/o activation at the molecular level. Evidence for brain regional differences in CB(1) receptor signal transduction efficacy and agonist selectivity for G proteins will be summarized. The possibility that CB(1) receptors interact with Gs or Gq will be evaluated, and questions with regard to the constitutive activity and G protein sequestration will be posed.

Figure 1

Ternary complex equilibrium model for agonist (A)–receptor (R)–G protein (G) interactions, coupled with the G protein activation cycle. Details with regard to the mechanisms depicted here are provided in the text. According to the ternary complex model, receptors (R), G proteins (G) and ligands can form an equilibrium (depicted within the box). The free CB₁ receptor (R) and the CB₁ receptor-Gα complex (RG_GDP) exist in equilibrium in the absence of exogenously added agonist (A) or inverse agonist (I) ligands (central box). This facile association is believed to be responsible for the constitutive activity reported for CB₁ receptors. The influence of agonist ligands (A) or inverse agonist ligands (I) on this equilibrium expands the equilibrium to include the AR and ARG_GDP complexes (main box) or the IR and IRG_GDP complexes (upper box). Outside the ternary complex equilibrium box, GTP and its analogs exchange for GDP in the absence of agonists (R^*G_ and R^*G_GTPγS) or in the presence of agonists (AR^*G_ and AR^*G_GTPγS. The presence of GTP or its analog facilitates dissociation of the Gαi and Gβγ proteins from the receptors. The activation cycle is reinitiated by the hydrolysis of GTP, and recombination of Gαi and Gβγ proteins to form the heterotrimer (G_GDP). GTPγS alone can promote dissociation of the G proteins from the CB₁ receptor, indicating that some RG_GDP complexes can spontaneously become activated in the absence of agonists, allowing GDP release (transiently empty G protein R^*G_) and GTPγS binding. Once GTPγS binds, the Gα_GTPγS dissociates irreversibly and the GTPγS cannot be hydrolyzed, such that the Gα_GTPγS can no longer re-enter the equilibrium reaction. In the presence of an inverse agonist (I), the IR and IRG_GDP complexes exist. The IRG_GDP is believed to form an inactive complex, which in the figure is depicted as exiting the ternary complex equilibrium box, and sequestering G proteins in an inactive (IR^oG_GDP) state. This state was originally proposed by Bouaboula et al. (1997) to describe a mechanism for the CB₁ receptor to ‘sequester' Gi proteins, thereby explaining their data that basal signal transduction through the MAPK or adenylyl cyclase pathways were blocked in the presence of SR141716 (see text).