P2 Receptors: P2Y G-Protein Family Overview

Once known as P2 purinoreceptors, surface receptors for extracellular nucleotides are now called P2 receptors. This subtle change in nomenclature reflects the more varied nature of nucleotidic ligands, other than those containing a purine moiety, that are capable of activating these surface receptors. The current nomenclature system for P2 receptors also is based on their molecular structure and signal transduction mechanisms, so defining a family of metabotropic P2 receptors (P2Y G protein-coupled receptors, GPCRs) and another family of ionotropic P2 receptors (P2X ligand-gated ion channels, LGICs).

The protein structure of the eight accepted members of the metabotropic P2Y family (P2Y1,2,4,6,11,12,13,14) is characterized by i) extracellular N-terminus and intracellular C-terminus, the former being glycosylated and the latter possessing consensus binding motifs for protein kinases, ii) seven a-helical transmembrane spanning regions (TM1-7) which form the ligand docking pocket, iii) a high level of sequence homology between key transmembrane spanning regions, notably TM3, TM6 and TM7, and iv) structural diversity of intracellular loops and C-terminus amongst P2Y subtypes, so influencing the degree of coupling with Gq/11, Gs and Gi proteins. Each P2Y receptor binds to a heterotrimeric G protein, frequently Gq/11, although P2Y11 can couple to both Gq/11 and Gs whereas P2Y12,13,14 couple preferentially to Gi. P2Y receptors also form heterotrimeric assemblies with adenosine (A1) receptors, and P2Y proteins may be capable of forming homodimeric assemblies. P2Y receptors are directed to discrete regions of cells that express multiple subtypes. Most cell types express more than one P2Y receptor subtype.

At the peptide level, P2Y receptors show a low level of sequence homology, notably over the region delimited by TM1 to TM7 where they are only 19-55% identical. Consequently, members of the P2Y family show significant differences in their pharmacological and operational profiles. Some P2Y receptors are activated principally by nucleoside diphosphates (P2Y1,6,12,13), while others are activated mainly by nucleoside triphosphates (P2Y2,4,11). Some P2Y receptors are activated by both purine and pyrimidine nucleotides (P2Y2,4,6,11), others by purine nucleotides alone (P2Y1,12,13) and, uniquely, P2Y14 is activated by ribose-nucleotides. Upon activation, recombinant P2Y receptors either activate phospholipase C and release intracellular calcium or affect adenylyl cyclase and alter cAMP levels. However, endogenous P2Y receptors show a wider diversity in intracellular signaling and can activate phospholipases A2, C and D, MEP/MAP kinase, PI-3 kinase, Rho-dependent kinase and tyrosine kinase. Also, endogenous P2Y receptors can couple either positively or negatively to adenylyl cyclase.

The eight P2Y receptors in the human genome belong to the assigned δ-of group the Rhodopsin-like GPCR superfamily which contains over 800 members. Analyses of primary sequence data indicates the presence in the δ-group of another 34 GPCRs that are structurally related to the eight, functionally-proven P2Y receptors. Unfortunately, some of these P2Y-like sequences have been misidentified as nucleotide receptors. For example, P2Y7 is now known to be a receptor for leukotriene B4; P2Y9 is a receptor for lysophosphatidic acid; P2Y15 is a receptor for the citric acid cycle intermediates, α-ketoglutarate and succinate. There is scant evidence to indicate that human P2Y5,10 sequences are nucleotide receptors and, therefore, they should viewed as orphan receptors. In mice, gene deletion has been achieved for P2Y1, P2Y2, P2Y4, P2Y12 and P2Y13. None are lethal, but knockout of either P2Y1 or P2Y12 genes results in bleeding disorders. Disruption of P2Y2 or P2Y4 genes alters solute transport and secretion in epithelial cells.

The table below contains accepted modulators and additional information. For a list of additional products, see the similar Products section below.


a) The P2Y1-n series comprises 15 putative G protein-coupled receptors, but only 8 are accepted as nucleotide receptors: P2Y3 may be an ortholog of P2Y6; P2Y5,10 are not yet proven to be functional P2 receptors; P2Y7 is a LTB4 leukotriene receptor; P2Y9 is a receptor for lysophosphatidic acid; P2Y15 is a receptor for the citric acid cycle intermediates, α-ketoglutarate and succinate; another receptor (turkey p2y) may be related to P2Y4; P2Y8 (532 aa) was cloned from Xenopus laevis, where it occurs mainly in early development during neurogenesis and is activated by ATP, UTP and CTP, and weakly antagonized by suramin.

b) In human, P2Y11 exists as several isoforms of a chimeric receptor generated by intergenic splicing between the SSF1 and P2Y11 genes on chromosome 19p31.

c) P2Y12 is the previously named P2YAC receptor that couples negatively to adenylyl cyclase.

d) P2YAp4A is a temporary name until the P2D receptor is cloned.

e) The P2YT receptor is best fitted by a three-receptor model comprising P2Y12 coupled negatively to adenylyl cyclase, P2Y1 activating phospholipase C and P2X1 coupled to an ion-channel permeable to Na+ and Ca2+ ions.

f) VTR15-20 is a truncated form of rat P2Y14, comprising 80% of the ORF for P2Y14.

g) ATP is a full agonist only at P2Y2,8,11, and a partial agonist or antagonist at human P2Y1. P2Y1,6,12,13 are activated preferentially by the nucleoside diphosphate, ADP.

h) Clopidogrel is a prodrug and converted into its active form by cytochrome P450.


A3P5PS: Adenosine 3´-phosphate 5´-phosphosulphate
ADPβS: Adenosine 5´-O-(2-thiodiphosphate)
AMPαS: Adenosine 5´-O-(thiomonophosphate)
Ap3A: Diadenosine triphosphate
AR-C67085MX: 2-Propylthio-D-β,γ-dichloromethylene-ATP
AR-C69931MX: N6-[2-(Methylthio)-ethyl]-2-(3,3,3-trifluoropropyl)thio-5´-adenylic acid
dATP: Deoxy-adenosine 5´-triphosphate
C1330-7: N1-(6-Ethoxy-1,3-benzothiazol-2-yl-2-(7-ethoxy-4-hydroxy-2,2-dioxo-2H-2-6benzo[4,5][1,3]thiazolo[2,3-c][1,2,4]thiadiazin-3-yl)-2-oxo-1-ethanesulfonamide
IDP: Inosine 5´-diphosphate
INS37217: P(1)-(Uridine 5')-P(4)- (2'-deoxycytidine 5')tetraphosphate, tetrasodium salt
INS365: Diuridine tetraphosphate
2-MeSADP: 2-Methylthioadenosine-5´-diphosphate
2-MeSAMP: 2-Methylthioadenosine-5´-monophosphate
MRS 2179: 2´-Deoxy-N6-methyladenosine-3´,5´-bisphosphate
MRS 2279: (N)-Methanocarba-N6-methyl-2-chloro-2´-deoxyadenosine-3´,5´-bisphosphate
MRS2365: (N)-Methanocarba-2-Methylthioadenosine-5´-diphosphate
MRS2578: 1,4-di-(Phenylthioureido) butane
MRS2500: (N)-Methanocarba-N6-methyl-2-iodo-2'-deoxyadenosine-3',5'-bisphosphate
PPADS: Pyridoxal-5-phosphate-6-azophenyl-2´,4´-disulphonic acid
RB-2: Reactive blue 2
UDP: Uridine 5´ 🞎🞎 -diphosphate
UDPβS: Uridine 5´-O-(2-thiodiphosphate)
Up3U: Diuridine triphosphate
UTP: Uridine 5´-triphosphate
UTPγS: Uridine 5´-O-(3-thiotriphosphate)

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