Purinergic P2Y receptors: Molecular diversity and implications for treatment of cardiovascular diseases

Article ID	Journal	Published Year	Pages	File Type
8537003	Pharmacology & Therapeutics	2017	16 Pages	PDF

Abstract

Purinergic signaling, mediated mainly by G protein-coupled P2Y receptors (P2YRs), is now attracting attention as a new therapeutic target for preventing or treating cardiovascular diseases. Observations using mice with genetically modified P2YRs and/or treated with a pharmacological P2YR inhibitor have helped us understand the physiological and pathological significance of P2YRs in the cardiovascular system. P2YR-mediated biological functions are predominantly activated by mononucleotides released from non-adrenergic, non-cholinergic nerve endings or non-secretory tissues in response to physical stress or cell injury, though recent studies have suggested the occurrence of ligand-independent P2YR function through receptor-receptor interactions (oligomerization) in several biological processes. In this review, we introduce the functions of P2YRs and possible dimerization with G protein-coupled receptors (GPCRs) in the cardiovascular system. We focus especially on the crosstalk between uridine nucleotide-responsive P2Y6R and angiotensin (Ang) II type1 receptor (AT1R) signaling, and introduce our recent finding that the P2Y6R antagonist MRS2578 interrupts heterodimerization between P2Y6R and AT1R, thereby reducing the risk of AT1R-stimulated hypertension in mice. These results strongly suggest that targeting P2Y6R oligomerization could be an effective new strategy to reduce the risk of cardiovascular diseases.

Keywords

LTα RAAS PLCβ IP3 GPCR PKC AT1R BN-PAGE AMPK UTP GRK VCAM PDGF-B VEGFR PECAM GEF GLUT4 MLC VSMCs pCMBS ENT1 EDHF ICAP UDP FLNA PIP2 NHERF TGF-β ApnA lymphotoxin α Na+/H+ exchanger regulatory factor ADP NF-κB PI3K EGF eNOS TNFα LPS NFAT HUVEC AgRP LDLR cAMP ECs ENaC G protein-coupled receptor kinase inositol 1,4,5-trisphosphate Mϕ uridine 5′-diphosphate uridine 5′-triphosphate adenosine 5′-triphosphate adenosine 5′-diphosphate ATP Cyclic adenosine monophosphate Myocardial infarction angiotensin II type 1 receptor Apoe apolipoprotein E blue native-polyacrylamide gel electrophoresis Fluorescence resonance energy transfer bioluminescence resonance energy transfer FRET endothelial NO synthase BRET transforming growth factor-β Immunoprecipitation Par tumor necrosis factor α glucose transporter 4 Filamin A myosin light chain Human umbilical vein endothelial cells Vascular smooth muscle cells Endothelial cells Renin-angiotensin-aldosterone system epidermal growth factor Nuclear Factor of Activated T Cells guanine nucleotide exchange factor nuclear factor-κB Endothelium-derived hyperpolarizing factor Phosphatidylinositol 3-kinase phosphatidylinositol 4,5-bisphosphate Phospholipase Cβ lipopolysaccharide Macrophage intercellular adhesion molecule platelet endothelial cell adhesion molecule vascular cell adhesion molecule Nitric oxide protease activated receptor 5′-AMP-activated protein Kinase Protein kinase C diadenosine polyphosphate agouti-related peptide Epithelial Na+ channel vascular endothelial growth factor receptor low density lipoprotein receptor G protein-coupled receptor