A Gs-coupled purinergic receptor boosts ca 2+ influx and vascular contractility during diabetic hyperglycemia

Maria Paz Prada, Arsalan U. Syed, Olivia R. Buonarati, Gopireddy R. Reddy, Matthew A. Nystoriak, Debapriya Ghosh, Sergi Simo Olivar, Daisuke Sato, Kent C. Sasse, Sean M. Ward, Luis Fernando Santana, Yang Kevin Xiang, Johannes W Hell, Madeline Nieves-Cintrón, Manuel F Navedo

Research output: Contribution to journalArticle

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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 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.

Original languageEnglish (US)
Article numbere42214
JournaleLife
Volume8
DOIs
StatePublished - Mar 1 2019

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Purinergic Receptors
Cyclic AMP-Dependent Protein Kinases
Hyperglycemia
Blood Vessels
Glucose
Apyrase
Tissue
Experiments
Cells

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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A Gs-coupled purinergic receptor boosts ca 2+ influx and vascular contractility during diabetic hyperglycemia . / Prada, Maria Paz; Syed, Arsalan U.; Buonarati, Olivia R.; Reddy, Gopireddy R.; Nystoriak, Matthew A.; Ghosh, Debapriya; Simo Olivar, Sergi; Sato, Daisuke; Sasse, Kent C.; Ward, Sean M.; Santana, Luis Fernando; Xiang, Yang Kevin; Hell, Johannes W; Nieves-Cintrón, Madeline; Navedo, Manuel F.

In: eLife, Vol. 8, e42214, 01.03.2019.

Research output: Contribution to journalArticle

Prada, Maria Paz ; Syed, Arsalan U. ; Buonarati, Olivia R. ; Reddy, Gopireddy R. ; Nystoriak, Matthew A. ; Ghosh, Debapriya ; Simo Olivar, Sergi ; Sato, Daisuke ; Sasse, Kent C. ; Ward, Sean M. ; Santana, Luis Fernando ; Xiang, Yang Kevin ; Hell, Johannes W ; Nieves-Cintrón, Madeline ; Navedo, Manuel F. / A Gs-coupled purinergic receptor boosts ca 2+ influx and vascular contractility during diabetic hyperglycemia In: eLife. 2019 ; Vol. 8.
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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 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.",
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AU - Prada, Maria Paz

AU - Syed, Arsalan U.

AU - Buonarati, Olivia R.

AU - Reddy, Gopireddy R.

AU - Nystoriak, Matthew A.

AU - Ghosh, Debapriya

AU - Simo Olivar, Sergi

AU - Sato, Daisuke

AU - Sasse, Kent C.

AU - Ward, Sean M.

AU - Santana, Luis Fernando

AU - Xiang, Yang Kevin

AU - Hell, Johannes W

AU - Nieves-Cintrón, Madeline

AU - Navedo, Manuel F

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