Elevated glucose increases vascular reactivity by promoting L-type Ca V 1.2 channel (LTCC) activity by protein kinase A (PKA). Yet, how glucose activates PKA is unknown. We hypothesized that a G s -coupled P2Y receptor is an upstream activator of PKA mediating LTCC potentiation during diabetic hyperglycemia. Experiments in apyrase-treated cells suggested involvement of a P2Y receptor underlying the glucose effects on LTTCs. Using human tissue, expression for P2Y 11 , the only G s -coupled P2Y receptor, was detected in nanometer proximity to Ca V 1.2 and PKA. FRET-based experiments revealed that the selective P2Y 11 agonist NF546 and elevated glucose stimulate cAMP production resulting in enhanced PKA-dependent LTCC activity. These changes were blocked by the selective P2Y11 inhibitor NF340. Comparable results were observed in mouse tissue, suggesting that a P2Y 11 -like receptor is mediating the glucose response in these cells. These findings established a key role for P2Y 11 in regulating PKA-dependent LTCC function and vascular reactivity during diabetic hyperglycemia.
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Immunology and Microbiology(all)