The role of G protein-coupled receptor kinases in GLP-1R β-arrestin recruitment and internalisation

Mar 10, 2024Biochemical pharmacology

How G protein-coupled receptor kinases influence GLP-1 receptor's beta-arrestin binding and internalization

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Abstract

GLP-1 receptor internalisation is dependent on the expression of G protein-coupled receptor kinases (GRKs).

GLP-1R internalisation occurs through a unique process that does not involve β-arrestins.
Knocking out GRKs using CRISPR/Cas9 affects the internalisation and recruitment of β-arrestins to the GLP-1R.
β-arrestin 1 recruitment is more sensitive to the absence of GRKs compared to β-arrestin 2.
Overexpression of GRK2, GRK3, GRK5, or GRK6 can restore β-arrestin 1 recruitment and internalisation to similar levels.
No specific GRK isoform has been identified as the sole driver of GLP-1R signalling pathways.

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The glucagon-like peptide 1 receptor (GLP-1R) is a validated clinical target for the treatment of type 2 diabetes and obesity. Unlike most G protein-coupled receptors (GPCRs), the GLP-1R undergoes an atypical mode of internalisation that does not require β-arrestins. While differences in GLP-1R trafficking and β-arrestin recruitment have been observed between clinically used GLP-1R agonists, the role of G protein-coupled receptor kinases (GRKs) in affecting these pathways has not been comprehensively assessed. In this study, we quantified the contribution of GRKs to agonist-mediated GLP-1R internalisation and β-arrestin recruitment profiles using cells where endogenous β-arrestins, or non-visual GRKs were knocked out using CRISPR/Cas9 genome editing. Our results confirm the previously established atypical β-arrestin-independent mode of GLP-1R internalisation and revealed that GLP-1R internalisation is dependent on the expression of GRKs. Interestingly, agonist-mediated GLP-1R β-arrestin 1 and β-arrestin 2 recruitment were differentially affected by endogenous GRK knockout with β-arrestin 1 recruitment more sensitive to GRK knockout than β-arrestin 2 recruitment. Moreover, individual overexpression of GRK2, GRK3, GRK5 or GRK6 in a newly generated GRK2/3/4/5/6 HEK293 cells, rescued agonist-mediated β-arrestin 1 recruitment and internalisation profiles to similar levels, suggesting that there is no specific GRK isoform that drives these pathways. This study advances mechanistic understanding of agonist-mediated GLP-1R internalisation and provides novel insights into how GRKs may fine-tune GLP-1R signalling.

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The role of G protein-coupled receptor kinases in GLP-1R β-arrestin recruitment and internalisation

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