Journal Article

Insights into cannabinoid receptor 2 (CB2) anterograde trafficking and pharmacological chaperoning

Woodhouse, Braden, Wood, Karren C., Glass, Michelle, Oyagawa, Caitlin R. M., Grimsey, Natasha L.

2025

Overview

Cannabinoid Receptor 2 (CB 2 ) is a promising therapeutic target for modulating inflammation. Canonical signalling responses to receptor ligands are critically dependent on cell surface receptor expression. However, it is also now appreciated that intracellular G protein-coupled receptors can contribute to signalling responses and influence functional outcomes. Therefore, understanding how the subcellular distribution of receptors is controlled is also highly pertinent. CB 2 is observed to be expressed at the cell surface as well as having a considerable proportion expressed intracellularly. Despite this distribution being well established, little is known about the regulation of CB 2 anterograde trafficking and subcellular distribution. We report that sustained treatment with a range of CB 2 agonists and inverse agonists stimulates a distinct population of CB 2 to be delivered to the cell surface, at various expression levels and despite agonists concurrently internalising cell surface CB 2 . We present evidence that this ligand-stimulated anterograde trafficking is a result of CB 2 agonists, as well as inverse agonists, acting as pharmacological chaperones. We also report that a di-lysine (KK) motif in the CB 2 C-terminal tail is required for basal delivery to the cell surface. Corroborating the hypothesis that CB 2 ligands can act as pharmacological chaperones, sustained CB 2 ligand stimulation induces cell surface expression of the mutated receptor and alters maturation states as measured by western blotting. Our finding that prolonged exposure to CB 2 ligands can induce CB 2 cell surface delivery via pharmacological chaperoning may well have important implications for optimal design of CB 2 -targeted therapeutics.

• Publisher: Springer International Publishing,Springer Nature B.V,Springer
• Subject: Animals / Antibodies / Biochemistry / Biomedical and Life Sciences / Biomedicine / Cannabinoid CB2 receptors / Cannabinoid Receptor Agonists - pharmacology / Cannabinoid receptor modulators / cannabinoid receptors / Cannabinoids / Cell Biology / Cell Membrane - metabolism / Cell surface / Cell surface receptors / Cells / Chaperones / G protein-coupled receptors / HEK293 Cells / Humans / inflammation / Intracellular signalling / Intracellular trafficking / Inverse agonists / Life Sciences / Ligands / Lysine / Molecular Chaperones - metabolism / Molecular mechanisms of pharmacological action / Original Article / Pharmacological chaperone / Pharmacology / Plasmids / Protein Transport - drug effects / Receptor, cannabinoid, CB2 / Receptor, Cannabinoid, CB2 - agonists / Receptor, Cannabinoid, CB2 - genetics / Receptor, Cannabinoid, CB2 - metabolism / Receptors / Receptors, G-Protein-Coupled / Signal Transduction / Therapeutic targets / therapeutics / Western blotting