A G(s)-coupled purinergic receptor boosts Ca2+ influx and vascular contractility during diabetic hyperglycemia
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Authors
Prada, Maria P.
Syed, Arsalan U.
Buonarati, Olivia R.
Reddy, Gopireddy R.
Nystoriak, Matthew A.
Ghosh, Debapriya
Simo, Sergi
Sato, Daisuke
Sasse, Kent C.
Ward, Sean M.
Issue Date
2019
Type
Article
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Abstract
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 P2Y(11) 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.
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Citation
Prada, M. P., Syed, A. U., Buonarati, O. R., Reddy, G. R., Nystoriak, M. A., Ghosh, D., É Navedo, M. F. (2019). A Gs-coupled purinergic receptor boosts Ca2+ influx and vascular contractility during diabetic hyperglycemia. eLife, 8. doi:10.7554/elife.42214
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Creative Commons Attribution 4.0 International
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ISSN
2050-084X