Update of P2Y receptor pharmacology: IUPHAR Review 27

Abstract

Eight G protein-coupled P2Y receptor subtypes respond to extracellular adenine and uracil mononucleotides and dinucleotides. P2Y receptors belong to the δ group of rhodopsin-like GPCRs and contain two structurally distinct subfamilies: P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 , and P2Y 11 (principally G q protein-coupled P2Y 1 -like) and P2Y 12-14 (principally G i protein-coupled P2Y 12 -like) receptors. Brain P2Y receptors occur in neurons, glial cells, and vasculature. Endothelial P2Y 1 , P2Y 2 , P2Y 4 , and P2Y 6 receptors induce vasodilation, while smooth muscle P2Y 2 , P2Y 4 , and P2Y 6 receptor activation leads to vasoconstriction. Pancreatic P2Y 1 and P2Y 6 receptors stimulate while P2Y 13 receptors inhibits insulin secretion. Antagonists of P2Y 12 receptors, and potentially P2Y 1 receptors, are anti-thrombotic agents, and a P2Y 2 /P2Y 4 receptor agonist treats dry eye syndrome in Asia. P2Y receptor agonists are generally pro-inflammatory, and antagonists may eventually treat inflammatory conditions. This article reviews recent developments in P2Y receptor pharmacology (using synthetic agonists and antagonists), structure and biophysical properties (using X-ray crystallography, mutagenesis and modelling), physiological and pathophysiological roles, and present and potentially future therapeutic targeting.Abbreviations: BMD, bone mineral density; DUSP, dual specificity protein phosphatase; ECL, extracellular loop; EPAC, exchange protein activated by cAMP; KO, knockout; MSD, musculoskeletal disorder; SNP, single nucleotide polymorphism; SS, Sjögren's syndrome; TM, transmembrane helix.

P2Y2 and P2X4 Receptors Mediate Ca2+ Mobilization in DH82 Canine Macrophage Cells

“…To establish an agonist profile for functional P2 receptors in DH82 cells, nucleotides which have previously demonstrated activity towards P2 receptors from dogs, humans or rodents [39,40] were utilised to measure changes in intracellular Ca 2+ . These nucleotides were ATP, 3 -O-(4-benzoyl)benzoyl-ATP (BzATP), adenosine-5 -diphosphate (ADP), 2-methylthio-ADP (2MeSADP), uridine-5 -triphosphate (UTP) and uridine-5 -diphosphate (UDP).…”

Purinergic signaling in infectious diseases of the central nervous system

“…The P2Y family is also composed of G protein-coupled receptors. Currently, there are eight distinct P2Y subtypes cloned and characterized in mammals: P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 , P2Y 11 , P2Y 12 , P2 13 , and P2Y 14 (Jacobson et al, 2020;Ralevic and Burnstock, 1998). Seven ionotropic receptors form the P2X family (P2X1-P2X7).…”

Purinergic System Signaling in Metainflammation-Associated Osteoarthritis

“…Pharmacology recognizes two families of purinergic receptors: P1 receptors, selective for adenosine ( 20 ), and P2 receptors, selective for nucleotides and dinucleotides of purines and pyrimidines ( 21 ).…”

“…P2X receptors are homo- or heterotrimers, which combine differently (e.g., P2X2/3, P2X1/2, P2X1/5, P2X2/6, P2X4/6, and P2X1/4) and form an ion channel for Na + , K + and Ca 2+ ( 18 , 23 ). P2Y receptors (P2Y1/2/4/6/11/12/13/14) are selective for ATP, ADP, UTP, and UDP, and couple with G proteins ( 21 ). Like adenosine receptors, P2Y receptors are internalized by β-arrestin, resulting in desensitization of the purinergic signal ( 18 , 23 , 24 ) ( Figure 1 ).…”