A quantitative pharmacology model for cannabinoid receptor type 1 (CB1 ) mediated by Gi/Gs protein competition

Br J Pharmacol. 2023 Dec 10. doi: 10.1111/bph.16293. Online ahead of print.

ABSTRACT

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.

EXPERIMENTAL APPROACH: 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.

KEY RESULTS: 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.

PMID:38072805 | DOI:10.1111/bph.16293