GRK3 is a G protein-coupled receptor kinase that phosphorylates ligand-bound GPCRs, leading to receptor desensitization, internalization, and signal termination 1. GRK3 demonstrates tissue-specific and context-dependent functions with significant clinical relevance. In cardiac pathology, GRK3 is the predominant GRK upregulated in diabetic hearts, where it phosphorylates cannabinoid receptor 2 (CB2R) at serine 335, promoting CB2R degradation and exacerbating diabetic cardiac injury; GRK3 knockout protects against hyperglycemia-induced heart damage 2. GRK3 also participates in μ-opioid receptor signaling through selective activation by Gβ5, facilitating β-arrestin recruitment to the plasma membrane 3. Notably, GRK3 exhibits tissue-protective roles in other contexts: reduced GRK3 expression correlates with hypertension and inverse associations with blood pressure 4, while GRK3 deficiency enhances osteoclastogenesis and Paget's disease-like bone lesions 5. GRK3 deficiency also triggers psychosis-related phenotypes including elevated brain IL-1β and increased dopamine neuron firing 6. Conversely, GRK3 overexpression drives aggressive gastric cancer through YAP1 pathway activation 7, identifying GRK3 as a poor prognostic marker and therapeutic target in cancer. GRK3's diverse pathological roles make it a promising target for multiple disease indications.