GRK4 Gene: Function, Mutations, and Role in Hypertension | NCBI Ensembl UniProt

GRK4 encodes a member of the G protein-coupled receptor kinase (GRK) subfamily that specifically phosphorylates agonist-occupied G protein-coupled receptors (GPCRs). GRK4 is highly expressed in the kidney and plays a critical role in desensitizing dopamine D1 receptors, thereby regulating renal sodium excretion and blood pressure. Genetic variants in GRK4 have been associated with essential hypertension and impaired natriuresis.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• GPCR downstream signaling (Reactome: R-HSA-388396)

• Dopamine receptor signaling (KEGG: hsa04728)

• Class A/1 (Rhodopsin-like receptors) (Reactome: R-HSA-373076)

GRK4 is a 578-amino acid serine/threonine kinase that phosphorylates agonist-bound GPCRs, initiating receptor desensitization and internalization. It contains an N-terminal RGS-like domain, a central kinase domain, and a C-terminal lipid-binding domain. GRK4 is predominantly expressed in the kidney and testis. Its primary physiological role is the regulation of renal dopamine D1 receptors, where gain-of-function variants impair natriuresis and contribute to hypertension.