Constitutive internalization across therapeutically targeted GPCRs correlates with constitutive activity.

Abstract:

:While the physiological function and mechanisms of agonist-dependent G protein-coupled receptor (GPCR) internalization have been extensively studied, the functional characterization of constitutive internalization of these critically important receptors has received less attention. Here we relate the constitutive internalization of more than 30 therapeutically targeted GPCRs to their agonist-induced internalization. The constitutive internalization ranges from levels of bulk membrane endocytosis in some cases to levels of agonist-induced internalization for other receptors. Moreover, for receptors with high constitutive internalization this occludes further agonist-induced internalization. Additionally, Gq-coupled GPCRs show a significantly higher rate of constitutive internalization than Gs- and Gi-coupled receptors. Finally, we consolidate the proposed link between the constitutive internalization, as assessed by a cytometry-based assay, and the constitutive activity of these receptors, as previously reported by a β-arrestin recruitment assay across the range of pharmacologically relevant receptors. In summary, we provide a quantitative comparison of GPCR internalization across a range of pharmacologically relevant receptors providing generalized insight into the relations between constitutive internalization, constitutive activity and agonist-induced internalization, which has so far relied on mutational studies in individual receptors.

authors

Hendrik Schmidt J,Perslev M,Bukowski L,Stoklund M,Herborg F,Herlo R,Lindegaard Madsen K

doi

10.1111/bcpt.13274

subject

Has Abstract

pub_date

2020-06-01 00:00:00

pages

116-121

eissn

1742-7835

issn

1742-7843

journal_volume

126 Suppl 6

pub_type

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