Differential Regulation of GPCRs-Are GRK Expression Levels the Key?

G protein-coupled receptors (GPCRs) comprise the largest family of transmembrane receptors and their signal transduction is tightly regulated by GPCR kinases (GRKs) and beta-arrestins. In this review, we discuss novel aspects of the regulatory GRK/beta-arrestin system. Therefore, we briefly revise the origin of the barcode hypothesis for GPCR/beta-arrestin interactions, which states that beta-arrestins recognize different receptor phosphorylation states to induce specific functions. We emphasize two important parameters which may influence resulting GPCR phosphorylation patterns: (A) direct GPCR-GRK interactions and (B) tissue-specific expression and availability of GRKs and beta-arrestins. In most studies that focus on the molecular mechanisms of GPCR regulation, these expression profiles are underappreciated. Hence we analyzed expression data for GRKs and beta-arrestins in 61 tissues annotated in the Human Protein Atlas. We present our analysis in the context of pathophysiological dysregulation of the GPCR/GRK/beta-arrestin system. This tissue-specific point of view might be the key to unraveling the individual impact of different GRK isoforms on GPCR regulation.

Automated summary

This review discusses the regulatory mechanisms of G protein-coupled receptors (GPCRs) by GPCR kinases (GRKs) and beta-arrestins, highlighting the importance of direct GPCR-GRK interactions and tissue-specific expression of GRKs and beta-arrestins in influencing GPCR phosphorylation patterns. The analysis of expression data for GRKs and beta-arrestins in different tissues provides insights into the pathophysiological dysregulation of the GPCR/GRK/beta-arrestin system, indicating the potential key role of tissue-specific perspectives in understanding the individual impact of different GRK isoforms on GPCR regulation.