GRK4 is a G protein-coupled receptor kinase that phosphorylates activated GPCRs, with isoform-specific functions: GRK4-alpha phosphorylates rhodopsin and is inhibited by calmodulin, while GRK4-gamma phosphorylates dopamine receptor D3 and D1 1. GRK4 regulates blood pressure through GPCR-mediated control of renal and arterial function, with genetic variants (R65L, A142V, A486V) associated with salt-sensitive hypertension across multiple ethnic groups 2. Mechanistically, GRK4 hyperphosphorylates and desensitizes D1R and D3R, impairing their natriuretic function 1. Beyond hypertension, GRK4 has emerged as pathogenic in myocardial infarction, where overexpression increases cardiomyocyte injury by suppressing autophagy through HDAC4 phosphorylation and reducing beclin-1 expression 3. In kidney ischemia-reperfusion injury, GRK4 exacerbates damage via STAT1 phosphorylation, triggering necroptosis through RIPK1/RIPK3/MLKL signaling 4. Recently, GRK4 was identified as a novel susceptibility gene for COPD, potentially influencing disease risk through inflammatory pathways 5. However, CPIC guidelines indicate insufficient evidence for GRK4 genotype-guided beta-blocker dosing 6, despite GRK4's role in ADRB2 phosphorylation and blood pressure regulation.