P2 Receptors: P2Y G-Protein Family

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.

 

Current Namea P2Y1 P2Y2 P2Y4 P2Y6
Alternate Name P2Y P2U Pyrimidinoceptor Pyrimidinoceptor
Structural Information 372 aa (human) 376 aa (human) 365 aa (human) 328 aa (human)
Selective Agonistsg ADPβS (A8016)
2-MeSADP (M152)
2-MeSATP (A023)
MRS 2365
PAPET-ATP
UTP (U1006)
UTPγS
ATPγS (A1388)
INS 37217
INS 365
UTP (U1006)
INS 37217
INS 365
UDP (U4125)
UDPβS
Up3U
5-BrUDP
IDP (I4375)
Selective Antagonists A3P5PS (A1651)
BzATP (B6396)
PPADS (P178)
MRS 2179 (M3808)
MRS 2279
MRS 2500
RB-2
Suramin (S2671)
Suramin (S2671) PPADS (weak) (P178)
ATP (human) (A2383)
RB-2 (rat)
BzATP (rat) (B6396)
MRS 2578 (M0319)
RB-2
PPADS (P178)
Suramin (S2671)
Signal Transduction Mechanisms Gq/11 (increase IP3/DAG)
possibly Gi
Gq/11 (increase IP3/DAG)
possibly Gi
Gq/11 (increase IP3/DAG)
Gq/11 (increase IP3/DAG)
Radioligands of Choice [3H]-MRS 2279 Not Known Not Known Not Known
Tissue Expression Platelets, endothelia, smooth muscle, CNS neurons, astrocytes, DRG neurons, osteoblasts, β-islet cells Epithelia, endothelia, smooth muscle, pituitary, astrocytes, hepatocytes Epithelia, smooth muscle, CNS neurons, astrocytes, retina, cochlea, placenta Epithelia, smooth muscle, heart, gall-bladder, retina, cochlea, placenta, spleen, monocytes
Physiological Function Ca-release, platelet shape change, SM relaxation, transmitter release Ca-release, Cl- secretion, SM hyperplasia, ciliary beating, hormone release Ca-release, Cl- secretion, GIRK inhibition, endolymph K+-gradient Ca-release, Cl- secretion, GIRK inhibition, IL-8 secretion
Disease Relevance Bleeding disorders, hypotension, stroke, epilepsy, osteoporosis, Type II diabetes Cystic fibrosis, chronic bronchitis, dry eye, SM proliferation, reactive gliosis Diarrhoea, GI malabsorption, brain water homeostasis, SM antiproliferation, hearing defects Inflammatory bowel disease, inflammation, atherosclerosis, cholestasis/gallstones, hearing defects

 

 

Current Namea P2Y11b P2Y12c P2Y13 P2Y14 P2YAp4Ad
Alternate Name PY P2YT or P2Te, SP1999 GPR 86 GPR 105, KIAA0001,
VTR 15-20f
P2D
Structural Information 371 aa (human) 342 aa (human) 333 aa (human) 338 aa (human) Not Known
Selective Agonistsg AR-C67085MX
dATP (D6500)
ADPβS (A8016)
BzATP (B6396)
α,β-MeATP (M6517)
2-MeSADP (M152)
ADP (A5285)
ADPβS (A8016)
Ap3A (D1387)
IDP (I4375)
2-MeSADP (M152)
ADP (A5285)
ADPβS (A8016)
Ap3A (D1387)
IDP (I4375)
UDP-glucose (U4625)
UDP-galactose (U4500)
UDP-N-acetylglucosamine
(U4375)
Ap4A (D1262)
Selective Antagonists Suramin (S2671)
RB-2
AMPαS (A1640)
AR-C67085MX
AR-C69931MX
C1330-7
2-MeSAMP (M1434)
BzATP (B6396)
RB-2
Suramin (S2671)
Clopidogrelh (C0614)
AR-C67085MX
AR-C69931MX
Ap4A (D1262)
2-MeSAMP (M1434)
PPADS (P178)
RB-2
Suramin (S2671)
MRS2211
Not Known Ip5I
Signal Transduction Mechanisms Gq/11 (increase IP3/DAG)
Gs (increase in cAMP)
Gi (cAMP modulation) Gi (cAMP modulation) Gi (cAMP modulation) Gq/11 (increase IP3/DAG)
Radioligands of Choice Not Known β-[32P]-2-MeSADP β-[32P]-2-MeSADP Not Known [3H]-Ap4A
Tissue Expression Epithelia, endothelia, smooth muscle, granulocytes, dendritic cells, spleen, kidney Blood platelets, chromaffin cells, glia, microglia Glia, spleen, lymph nodes, bone marrow, dendritic cells Placenta, adipose tissue, stomach & intestine, glia, astrocytes, neutrophils. Lymphocytes, hemopoietic stem cells, dendritic cells Not Known
Physiological Function Ca-release, Cl- secretion, cAMP elevation, renin secretion, IL-12 secretion cAMP modulation, Ca-channel inhibition, haemostasis cAMP modulation, haematopoiesis, immune responses cAMP modulation, neuroimmune responses, chemoattraction, immune responses Not Known
Disease Relevance SM proliferation, neutropenia, leukaemia, inflammation, diabetic nephropathy Thromboembolism, diabetic thromboembolism, cardiovascular disease Not Known Reactive astroglioisis, inflammation, tumor recognition Not Known

 

Footnotes

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.

 

Abbreviations

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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References