G protein-coupled receptor kinase (GRK)

G protein-coupled receptor kinases (GRKs) are a family of seven serine/threonine kinases (GRK1-7) that serve as critical negative regulators of G protein-coupled receptor (GPCR) signaling. Upon receptor activation, GRKs phosphorylate the intracellular domains of the GPCR, which facilitates the recruitment of arrestin proteins. This process sterically hinders G protein coupling, leading to signal desensitization, and initiates receptor internalization via clathrin-coated pits (PMID: 29054319). While GRK2 and GRK5 are the most extensively studied members due to their roles in cardiovascular homeostasis, the broader family includes specialized isoforms like GRK1 (rhodopsin kinase) and GRK7, which are essential for visual signal termination (PMID: 26116620). Dysregulation of GRK expression is a hallmark of several diseases; for instance, elevated GRK2 levels in the heart contribute to the chronic desensitization of beta-adrenergic receptors in heart failure (PMID: 23149224). Furthermore, GRKs have been implicated in cancer progression and neurodegenerative disorders like Parkinson's disease by modulating non-canonical signaling pathways involving AKT, MAPK, and p53. Therapeutic targeting of GRKs is an active area of research, with small molecules such as the SSRI paroxetine being repurposed as GRK2 inhibitors to improve cardiac function (PMID: 22649039). However, the high structural conservation of the kinase domain across the family poses significant challenges for developing isoform-selective inhibitors that avoid systemic safety concerns related to widespread GPCR overstimulation (PMID: 25338665).

Other names

GPCR kinaseBeta-adrenergic receptor kinaseB-ARKGRKsG protein-coupled receptor kinase family

Inhibition of the kinase activity of GRKs to prevent the phosphorylation of activated G protein-coupled receptors, thereby blocking arrestin recruitment and subsequent receptor desensitization and internalization.