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: P2Y₁ , P2Y₂ , P2Y₄ , P2Y₆ , and P2Y₁₁ (principally G_q protein-coupled P2Y₁ -like) and P2Y_12-14 (principally G_i protein-coupled P2Y₁₂ -like) receptors. Brain P2Y receptors occur in neurons, glial cells, and vasculature. Endothelial P2Y₁ , P2Y₂ , P2Y₄ , and P2Y₆ receptors induce vasodilation, while smooth muscle P2Y₂ , P2Y₄ , and P2Y₆ receptor activation leads to vasoconstriction. Pancreatic P2Y₁ and P2Y₆ receptors stimulate while P2Y₁₃ receptors inhibits insulin secretion. Antagonists of P2Y₁₂ receptors, and potentially P2Y₁ receptors, are anti-thrombotic agents, and a P2Y₂ /P2Y₄ 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.

FIGURE 1

P2Y receptor ligands. (a) Natural agonists of P2Y receptors . (b) P2Y₁ receptor agonists and antagonists. (c) P2Y₂ receptor agonists and antagonist. (d) P2Y₄ receptor agonists and antagonists

FIGURE 2

P2Y receptor ligands. (a) P2Y₆ receptor agonists and antagonists. (b) P2Y₁₁ receptor agonists and antagonists. (c) P2Y₁₂ receptor agonists and antagonists. (d) P2Y₁₃ receptor antagonist. (e) P2Y₁₄ receptor agonists and antagonists

FIGURE 3

(a) Evolutionary relationships of human P2Y₁‐ and P2Y₁₂‐like receptors of the δ group of rhodopsin‐like GPCRs (Fredriksson & Schiöth, 2005). P2Y₁‐ and P2Y₁₂‐like receptors form separated clusters of receptors indicating that they evolved independently. The evolutionary history was inferred using the neighbour‐joining method by extending a previous analyses (Le Duc et al., 2017). The optimal tree with the sum of branch length = 14.64350117 is shown. The tree is drawn to scale, with branch lengths in the same units as those of the evolutionary distances used to infer the phylogenetic tree. The evolutionary distances were computed using the Poisson correction method and are in the units of the number of amino acid substitutions per site. The analysis involved the amino acid sequences of 30 human receptors which were aligned by using the PAM matrix and default parameters. All positions with less than 95% site coverage were eliminated. That is, fewer than 5% alignment gaps, missing data, and ambiguous bases were allowed at any position. There were a total of 239 positions in the final dataset. Evolutionary analyses were conducted in MEGA7 (Kumar, Stecher, & Tamura, 2016). HCARx, hydroxycarboxylic acid receptors; LPARx, lysophosphatidic acid receptors; OXGR1, 2‐oxoglutarate receptor; SUCNR1, succinate receptor; PTAFR, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=334; P2Yx nucleotide receptors. (b) Genomic clustering of P2Y‐like receptors on chromosome 3 and chromosome X. Several P2Y receptors and other members of the δ group cluster at genomic loci, most prominent clusters at chromosome 3 and chromosome X. The P2Y₁₂ receptor‐like receptors are found in a MED12L gene intron at chromosome 3. Similarly, GPR34 and GPR82 are found in a reverse‐oriented CASK gene intron at Xp11.4. Phylogenetic analysis showed relation of cysteinyl‐LT receptor and lysophosphatidic acid receptors (see (a)). Interestingly, CysLT₂ and LPA₆ receptors and GPR183 are closely located at chromosome 13 (13q14.2, not shown) whereas CysLT₁ receptors genomically cluster with LPA₄, P2Y10 receptors, and GPR174 at the X chromosome

FIGURE 4

Structures of P2Y₁₂ receptors and P2Y₁ receptors. (a) Structure of the P2Y₁₂ receptor‐2MeSADP 8 complex. The P2Y₁₂ receptor is shown in blue cartoon representation. 2MeSADP is shown as blue spheres. The disulphide bonds are shown as yellow sticks. (b) Structure of the P2Y₁₂ receptor‐AZD1283 40 complex. The receptor is coloured green and shown in cartoon representation. AZD1283 is shown as spheres with pink carbons. The disulphide bridge is shown as pink sticks. (c) Structure of the P2Y₁ receptor‐BPTU complex. The P2Y₁ receptor is coloured cyan and shown as cartoon. The ligand BPTU is shown as spheres with green carbons. The disulphide bonds are shown as yellow sticks. (d) Structure of the P2Y₁ receptor‐MRS2500 10 complex. The P2Y₁ receptor is shown in orange cartoon representation. MRS2500 is shown as spheres with yellow carbons. The disulphide bonds are show as magenta sticks. (e) Structural comparison of the extracellular region in the P2Y₁₂ receptor‐2MeSADP and P2Y₁₂ receptor‐AZD1283 complexes. In the P2Y₁₂ receptor‐AZD1283 structure, the receptor is shown in green cartoon representation, the ligand AZD1283 is shown as pink sticks. In the P2Y₁₂ receptor‐2MeSADP structure, the receptor is shown in blue cartoon representation and 2MeSADP is shown as blue sticks. The black arrows indicate the movements of helices VI and VII in the 2MeSADP‐bound structure relative to the AZD1283‐bound structure. (f) Comparison of the binding pose of AZD1283 and 2MeSADP in P2Y₁₂ receptors. The colour scheme is the same as that in panel (e). (g) Comparison of the nucleotide binding modes in P2Y₁ receptors and P2Y₁₂ receptors. The P2Y₁ receptor is shown in yellow cartoon representation. MRS2500 and 2MeSADP are shown as yellow sticks and green carbon respectively