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Elife. 2019 Mar 1;8. pii: e42214. doi: 10.7554/eLife.42214.

A Gs-coupled purinergic receptor boosts Ca2+ influx and vascular contractility during diabetic hyperglycemia.

Author information

1
Department of Pharmacology, University of California, Davis, Davis, United States.
2
Diabetes & Obesity Center, Department of Medicine, University of Louisville, Kentucky, United States.
3
Department of Cell Biology & Human Anatomy, University of California, Davis, Davis, United States.
4
Sasse Surgical Associates, Reno, United States.
5
Department of Physiology & Cell Biology, University of Nevada, Reno, United States.
6
Department of Physiology & Membrane Biology, University of California, Davis, Davis, United States.
7
VA Northern California Healthcare System, Mather, United States.
#
Contributed equally

Abstract

Elevated glucose increases vascular reactivity by promoting L-type CaV1.2 channel (LTCC) activity by protein kinase A (PKA). Yet, how glucose activates PKA is unknown. We hypothesized that a Gs-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 P2Y11, the only Gs-coupled P2Y receptor, was detected in nanometer proximity to CaV1.2 and PKA. FRET-based experiments revealed that the selective P2Y11 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 P2Y11-like receptor is mediating the glucose response in these cells. These findings established a key role for P2Y11 in regulating PKA-dependent LTCC function and vascular reactivity during diabetic hyperglycemia.

KEYWORDS:

arterial tone; biosensors; cell biology; extracellular nucleotides; human; ion channels; molecular biophysics; mouse; structural biology

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