G Protein–Coupled Receptor Kinase 3 Exacerbates Diabetic Heart Injuries Through Direct Phosphorylation of Cannabinoid Receptor 2 in Humans and Mice
Authors' conclusion
GRK3 is the predominant GRK that aggravates diabetic heart injury. YY1-dependent upregulation of GRK3 functions through direct phosphorylation of CB2R.
Study context
- Population
- Human and mouse diabetic heart tissues; diabetic mouse models
Main finding
As reported in the abstract
- GRK3 was the predominant GRK, significantly upregulated in cardiomyocytes of human and mouse diabetic hearts
- GRK3 expression positively correlated with cardiac fibrosis and hypertrophy in human diabetic hearts
- Heart-restricted GRK3 overexpression aggravated, and cardiomyocyte conditional GRK3 knockout significantly relieved, hyperglycemia-induced heart injury
- Hyperglycemia upregulated GRK3 by inhibiting the transcriptional repressor YY1
- GRK3 phosphorylated CB2R at S335, promoting β-arrestin 2-mediated internalization and ubiquitin-dependent degradation of CB2R
- Modulation of YY1 or CB2R perturbed GRK3 functions in diabetic hearts
- Isochlorogenic acid A identified by virtual screening as an efficient GRK3 inhibitor protecting the heart from diabetic injury without additional side effects
Original publication
G Protein–Coupled Receptor Kinase 3 Exacerbates Diabetic Heart Injuries Through Direct Phosphorylation of Cannabinoid Receptor 2 in Humans and Mice. Circulation. Published 7 August 2025. doi:10.
Summarised from the published abstract; every number is checked against it