A quantitative pharmacology model for cannabinoid receptor type 1 (CB1) mediated by Gi/Gs protein competitionLiang Yang, David B. Finlay, Hayley M. Green, Xiao Zhu, Michelle Glass, Stephen Duffull
BACKGROUND AND PURPOSE
Orthosteric agonism of the CB1 receptor normally associates with Gi signalling resulting in a net inhibition of cAMP production. However, empirical evidence shows CB1 causes a net stimulation of cAMP through Gs coupling under two conditions: (i) co‐stimulation with the D2 receptor; (ii) high‐level CB1 expression. Two hypotheses have been proposed to account for this paradoxical effects (1) Gi is consumed by coupling to D2 or extra CB1, and excess CB1 binds to Gs, and (2) the formation of dimers CB1‐CB1 or CB1‐D2 switches Gi/Gs preference. This study explored the mechanisms of Gi/Gs preference based on a mathematical model of the CB1 receptor.
The model was established based on Hypothesis 1 and known mechanisms. The model was calibrated to align with multiple types of data (cAMP, Gi dissociation and internalisation). The key step of Hypothesis 1 was examined by simulation from the model. An experiment was proposed to distinguish Hypothesis 1 and 2.
The model successfully descripted multiple types of data under Hypothesis 1. Simulations from the model indicated that pre‐coupling of G‐protein with receptors is necessary to support this hypothesis. The model designed experiments to distinguish Hypothesis 1 and 2 by increasing Gi&Gs in parallel with CB1 overexpression. In this setting, the two hypotheses result in distinct cAMP responses.
CONCLUSION AND IMPLICATIONS
A mathematical model of CB1 regulated Gi/Gs pathways was developed. It indicated Hypothesis 1 is feasible and G protein pre‐coupling is a key step causing cAMP signalling switch. The model‐designed experiments provided guides for future experimentation research.