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Delineating the interactions between the cannabinoid CB2 receptor and its regulatory effectors; β-arrestins and G protein-coupled receptor kinases

Delineating the interactions between the cannabinoid CB2 receptor and its regulatory effectors; β-arrestins and G protein-coupled receptor kinases

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PATEL, Monica, Christoph MATTI, Natasha L. GRIMSEY, Daniel F. LEGLER, Jonathan A. JAVITCH, David B. FINLAY, Michelle GLASS, 2022. Delineating the interactions between the cannabinoid CB2 receptor and its regulatory effectors; β-arrestins and G protein-coupled receptor kinases. In: British Journal of Pharmacology (BJP). Wiley. 179(10), pp. 2223-2239. ISSN 0366-0826. eISSN 1476-5381. Available under: doi: 10.1111/bph.15748

@article{Patel2022-05Delin-55750, title={Delineating the interactions between the cannabinoid CB2 receptor and its regulatory effectors; β-arrestins and G protein-coupled receptor kinases}, year={2022}, doi={10.1111/bph.15748}, number={10}, volume={179}, issn={0366-0826}, journal={British Journal of Pharmacology (BJP)}, pages={2223--2239}, author={Patel, Monica and Matti, Christoph and Grimsey, Natasha L. and Legler, Daniel F. and Javitch, Jonathan A. and Finlay, David B. and Glass, Michelle} }

Glass, Michelle 2021-12-03T08:12:52Z Matti, Christoph Legler, Daniel F. Patel, Monica Finlay, David B. 2021-12-03T08:12:52Z Javitch, Jonathan A. Background and Purpose<br />The cannabinoid CB<sub>2</sub> receptor (CB<sub>2</sub>) is a promising therapeutic target for modulating inflammation. However, little is known surrounding the mechanisms underpinning CB<sub>2</sub> desensitisation and regulation, particularly the role of G protein-coupled receptor kinases (GRKs). Here, we evaluated the role of six GRK isoforms in β-arrestin recruitment to CB<sub>2</sub>. Mutagenesis of several distal C-terminal aspartic acid residues was also performed in an attempt to delineate additional structural elements involved in the regulation of CB<sub>2</sub>.<br /><br />Experimental Approach<br />In CB<sub>2</sub>-expressing HEK 293 cells, β-arrestin translocation was measured using real-time BRET assays. G protein dissociation BRET assays were performed to assess the activation and desensitisation of CB<sub>2</sub> in the presence of β-arrestin 2.<br /><br />Key Results<br />Overexpression of GRK isoforms 1-6 failed to considerably improve translocation of either β-arrestin 1 or β-arrestin 2 to CB<sub>2</sub>. Consistent with this, inhibition of endogenous GRK2/3 did not substantially reduce β-arrestin 2 translocation. Mutagenesis of C-terminal aspartic acid residues resulted in attenuation of β-arrestin 2 translocation, which translated to a reduction in desensitisation of G protein activation.<br /><br />Conclusion and Implications<br />Our findings suggest that CB<sub>2</sub> does not adhere to the classical GPCR regulatory paradigm, entailing GRK- and β-arrestin-mediated desensitisation. Instead, C-terminal aspartic acid residues may act as phospho-mimics to induce β-arrestin activation. This study provides novel insights into the regulatory mechanisms of CB<sub>2</sub>, which may aid in our understanding of drug tolerance and dependence. Patel, Monica Grimsey, Natasha L. Legler, Daniel F. Grimsey, Natasha L. Finlay, David B. eng 2022-05 Matti, Christoph Glass, Michelle terms-of-use Javitch, Jonathan A. Delineating the interactions between the cannabinoid CB2 receptor and its regulatory effectors; β-arrestins and G protein-coupled receptor kinases

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