A G-coupled Purinergic Receptor Boosts Ca Influx and Vascular Contractility During Diabetic Hyperglycemia

Overview

Journal Elife

Specialty Biology

Date 2019 Mar 2

PMID 30821687

Citations 27

Authors

Maria Paz Prada

Arsalan U Syed

Olivia R Buonarati

Gopireddy R Reddy

Matthew A Nystoriak

Debapriya Ghosh

Sergi Simo

Daisuke Sato

Kent C Sasse

Sean M Ward

Luis F Santana

Yang K Xiang

Johannes W Hell

Madeline Nieves-Cintron

Manuel F Navedo

Affiliations

Soon will be listed here.

Abstract

Elevated glucose increases vascular reactivity by promoting L-type Ca1.2 channel (LTCC) activity by protein kinase A (PKA). Yet, how glucose activates PKA is unknown. We hypothesized that a G-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, the only G-coupled P2Y receptor, was detected in nanometer proximity to Ca1.2 and PKA. FRET-based experiments revealed that the selective P2Y agonist NF546 and elevated glucose stimulate cAMP production resulting in enhanced PKA-dependent LTCC activity. These changes were blocked by the selective P2Y inhibitor NF340. Comparable results were observed in mouse tissue, suggesting that a P2Y-like receptor is mediating the glucose response in these cells. These findings established a key role for P2Y in regulating PKA-dependent LTCC function and vascular reactivity during diabetic hyperglycemia.

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