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P2Y2 receptor

Family: P2Y receptors

Contents:
Gene and Protein Information
Previous and Unofficial Names
Database Links
Agonists
Antagonists
Transduction Mechanisms
Tissue Distribution
Expression Datasets
Functional Assays
Physiological Functions
Physiological Consequences of Altering Gene Expression
Phenotypes, Alleles and Disease Models
Biologically Significant Variants
General Comments
References
Gene and Protein Information
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 377 11q13.5-q14.1 P2RY2 purinergic receptor P2Y, G-protein coupled, 2 46
Mouse 7 373 7 F1 P2ry2 purinergic receptor P2Y, G-protein coupled 2 40
Rat 7 374 1q32 P2ry2 purinergic receptor P2Y, G-protein coupled, 2 21,55
Previous and Unofficial Names
P2U
P2U
P2U1
P2Y2
ATP receptor
P2U purinoceptor 1
P2Y ATP receptor 2
P2Y purinoceptor 2
purinergic receptor P2Y, G-protein coupled 2
purinergic receptor P2Y, G-protein coupled, 2
Database Links
ChEMBL Target 11907 (Hs), 100428 (Rn)
DrugBank Target 4165 (Hs)
Ensembl ENSG00000175591 (Hs), ENSMUSG00000032860 (Mm), ENSRNOG00000019283 (Rn)
Entrez Gene 5029 (Hs), 18442 (Mm), 29597 (Rn)
GeneCards P2RY2 (Hs)
GenitoUrinary Development Molecular Anatomy Project P2ry2 (Mm)
HomoloGene 1927 (Hs)
Human Protein Reference Database 02499 (Hs)
InterPro P41231 (Hs), P35383 (Mm), P41232 (Rn)
KEGG Gene hsa:5029 (Hs), mmu:18442 (Mm), rno:29597 (Rn)
OMIM 600041 (Hs)
PharmGKB Gene PA32870 (Hs)
PhosphoSitePlus P41231 (Hs), P35383 (Mm), P41232 (Rn)
Protein Ontology (PRO) PRO:000001572 (Hs)
RefSeq Nucleotide NM_002564 (Hs), NM_008773 (Mm), NM_017255 (Rn)
RefSeq Protein NP_002555 (Hs), NP_032799 (Mm), NP_058951 (Rn)
TreeFam ENSG00000175591 (Hs), ENSMUSG00000032860 (Mm), ENSRNOG00000019283 (Rn)
UniGene Hs. 339 (Hs)
UniProt P41231 (Hs), P35383 (Mm), P41232 (Rn)
Wikipedia P2Y2 receptor
P2Y receptors
Search for 3D structures on the PDB
Search by keyword: P2Y receptors P2Y2 receptor Search by accession number: P41232, P41231, P35383
Natural/Endogenous Ligand(s)
ATP
UTP
Rank order of potency (Human)
UTP=ATP
Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
MRS2698 Hs Full agonist 8.1 pEC50 28
UTP Hs Full agonist 8.1 pEC50 30,37
4-thio-UTP Hs Full agonist 7.5 pEC50 7
2-thioUTP Hs Agonist 7.3 pEC50 19
ATP Hs Full agonist 7.1 pEC50 30,37
Up4U Hs Full agonist 7.0 pEC50 48
Up4dC Hs Full agonist 6.7 pEC50 63
Ap4A Hs Full agonist 6.1 pEC50 10,47
UTPγS Hs Full agonist 5.8 pEC50 37
5BrUTP Hs Full agonist 5.7 pEC50 37
MRS2768 Hs Full agonist 5.7 pEC50 32
Agonist Comments

Reference [37] EC50 values are found using IP3 functional assays.
References [48,63] EC50 values are found using Ca2+ functional assays.

A library of nucleotides triphosphate incorporating a C-linked unnatural base (i.e., benzothiazole, benzoxazole and benzimidazole) was synthesized, a number of which offer potency comparable to that of the N-linked series, and significantly more stable than UTP [15].
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
AR-C126313 Hs Antagonist 6.0 pEC50 28
reactive blue-2 Hs Antagonist 6.0 pIC50 29
suramin Hs Antagonist 4.3 pIC50 53
Antagonist Comments

    The rat P2Y2 is virtually insensitive to Reactive Blue 2 (pIC50 > 2) [7]

    Although non selective, suramin can be useful to discriminate between the P2Y2 and the P2Y4 receptor subtypes, the latter being insensitive to its antagonism [7]

    A small library of 1-amino-4-phenylamino-2-sulfoanthraquinone derivatives related to Reactive Blue 2 has been synthesized, and some of them proved to be potential P2Y2 antagonists with low micromolar IC50 values [59]

Explore drug-target interactions for this set of compounds using iPHACE

Primary Transduction Mechanisms
Transducer Effector/Response
Gq/G11 family Phospholipase C stimulation
Comments:  In bronchial and intestinal epithelia, activation of P2Y2 receptor subtype leads to stimulation of chloride secretion through Gq/G11, and phospholipase C activation followed by inhibition of Na+ transport [62], [17], [25]
References:  58,62
Secondary Transduction Mechanisms
Transducer Effector/Response
Gi/Go family
G12/G13 family 		Other - See Comments
Comments:  In hP2Y2-transfected 1321N1 cells, P2Y2 receptor was found to couple through integrins to Gi/Go, leading to Rac activation, vitronectin up-regulation and increasing cell migration [5], and to G12, leading to ρ activation, cofilin and myosin light chain-2 phosphorylation, stress fiber formation and chemotaxis towards UTP [39] Coupling of P2Y2 receptor to hematopoietic cell specific Gα16, belonging to the Gq family, was found in human erythroleukemia cells [34] In the presence of NGF, the interaction between the P2Y2 receptor and TrkA through Srk was detected, followed by activation of ERK1/2 [2-3]
References:  5,39
Tissue Distribution
middle ear epithelial cells
Species:  Human
Technique:  Immunohistochemistry
References:  12
bronchial epithelium
Species:  Human
Technique:  realtime PCR
References:  61
Brain: putamen, striatum > caudate nucleus, hypothalamus, medulla oblongata, substantia nigra, thalamus, spinal cord, locus coeruleus > amygdala, globus pallidus, hippocampus, nucleus accumbens, parahippocampal gyrus, superior frontal gyrus > cerebellum, cingulate gyrus > medial frontal gyrus.
Species:  Human
Technique:  RT-PCR.
References:  43
mucus-secreting cells of nasal epithelium
Species:  Rat
Technique:  Immunohistochemistry
References:  23
Aortic smooth muscle cells.
Species:  Rat
Technique:  Northern blotting.
References:  55
endolymphatic sac epithelia
Species:  Rat
Technique:  RT-PCR
References:  44
dorsal root ganglia neurons
Species:  Rat
Technique:  in situ hydridisation
References:  33
Liver > testis > esophagus > lung, trachea > heart, skeletal muscle > stomach, kidney.
Species:  Rat
Technique:  Northern blotting.
References:  21
Expression Datasets

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Log average relative transcript abundance in mouse tissues measured by qPCR from Regard, J.B., Sato, I.T., and Coughlin, S.R. (2008). Anatomical profiling of G protein-coupled receptor expression. Cell, 135(3): 561-71. [PMID:18984166] [Raw data: website]

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Functional Assays
The voltage-clamp technique was used to measure the ionic membrane currents in cultured mouse cumulus cell-enclosed oocytes (CEOs) in response to P2Y2 receptor agonists.
Species:  Mouse
Tissue:  Cultured cumulus cell-enclosed oocytes (CEOs).
Response measured:  Opening of Ca2+-dependent Cl- channels and Ca2+-independent Na+ channels. Subsequent depolarisation and opening of voltage-sensitive K+ channels.
References:  1
Measurement of [Ca2+]i in K-562 cells (human leukemia cells line) transfected with the human P2Y2 receptor.
Species:  Human
Tissue:  K-562.
Response measured:  Increase in [Ca2+]i.
References:  20
Measurement of IP3 levels in response to selective P2Y2 agonists in HEK 293 cells endogenously expressing the P2Y1 and P2Y2 receptors.
Species:  Human
Tissue:  HEK 293 cells.
Response measured:  IP3 accumulation.
References:  54
Measurement of [Ca2+]i in human glioma C6 cells endogenously expressing P2Y1 and P2Y2.
Species:  Human
Tissue:  Glioma C6 cells.
Response measured:  Increase in [Ca2+]i.
References:  52
Measurement of Ca2+ levels in response to the P2Y2 agonist UTP in mouse peritoneal macrophage cells.
Species:  Mouse
Tissue:  Peritoneal macrophages.
Response measured:  Increase in [Ca2+]i.
References:  13
Following mechanical stimulation of an individual 1321N1 cell, measurement of Ca2+ propagation in 1321N1 cells transfected with the P2Y2 cells.
Species:  Rat
Tissue:  1321N1 cells.
Response measured:  Ca2+ wave only spread to cells expressing the P2Y2 receptor. P2Y2 is not required for the initiation of the wave.
References:  22
Assay for the processing of amyloid precursor protein (APP) by P2Y2 receptors transfected into 1321N1 cells.
Species:  Human
Tissue:  1321N1 astrocytoma cells.
Response measured:  Release of sAPPα, dependent on extracellular Ca2+ levels.
References:  9
Measurement of Ca2+ levels and spontaneous transient outward current (STOCs) in vascular smooth muscle (A7r5) cells transfected with a chimer of the P2Y2 and green fluorescent protein (P2Y2-GFP).
Species:  Human
Tissue:  A7r5 cells.
Response measured:  Increase in [Ca2+]i levels and subsequent generation of STOCs.
References:  38
Modulation of amiloride-sensitive Na+ transport by PIP2 hydrolysis
Species:  Rat
Tissue:  Xenopus oocytes
Response measured:  inhibition of Na+ currents
References:  36
Physiological Functions
A study using P2Y2 knockout mice show that P2Y2 receptors are involved in the mediation of ion transport in the trachea and the gallbladder.
Species:  Mouse
Tissue:  Trachea and gallbladder.
References:  14
Control of cellular proliferation, spreading and migration.
Species:  Human
Tissue:  keratinocytes of the epidermis
References:  18,58
The P2Y2 receptor mediates the chloride secretory response in the jejunum along with the P2Y4 receptor.
Species:  Mouse
Tissue:  Jejunum.
References:  25
Increase in coronary blood flow by vasodilation.
Species:  Rat
Tissue:  Isolated heart.
References:  21
blockade of bone mineralization
Species:  Rat
Tissue:  primary osteoblasts
References:  45
stimulation of ciliary beat and Cl- secretion; modulation of mucin release
Species:  Human
Tissue:  airway epithelia
References:  16-17
activation of luminal K+ secretion
Species:  Mouse
Tissue:  Colon
References:  42
vasopressin-independent control of the osmotic water permeability of the inner medullary collecting duct of the kidney
Species:  Rat
Tissue:  inner madullary cells
References:  31,49,56-57,65
presynaptic inhibition of glutamate release
Species:  Rat
Tissue:  Hippocampus
References:  51
positive inotropism
Species:  Human
Tissue:  Heart
References:  60
inhibition of apoptosis
Species:  Rat
Tissue:  PC12 cells, dorsal root ganglia
References:  4
orientation of neutrophil chemotaxis
Species:  Human
Tissue:  neutrophils
References:  11
migration of vascular smooth muscle cells
Species:  Mouse
Tissue:  vascular smooth muscle cells
References:  64
Physiological Consequences of Altering Gene Expression
P2Y2 receptor knockout studies show that the P2Y2 receptor mediates most of the Cl- secretion in the trachea and around half in the gallbladder.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  14
P2Y2 receptor knockout mice exhibit abolished Ca2+ mobilisation in response to UTP.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  27
P2Y2 receptor knockout mice exhibit reduced K+ secretion in the luminal membrane of the distal colonic mucosa when compared to wild-type mice.
P2Y2/P2Y4 double knockout mice have completely abolished K+ secretion in the distal colonic mucosa.
Species:  Mouse
Tissue: 
Technique:  Transgenesis.
References:  42
P2Y2 receptor knockout mice exhibit a decreased chloride secretory response in the jejunum, but not the colon.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  25
Luminal colon UTP-stimulated K+ secretion was found completely absent in P2Y2/P2Y4 double receptor KO mice
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells
References:  42
P2Y1/P2Y2 double knock out mice showed an increased susceptibility to Pseudomonas aeruginosa infection (100% of death within 30 hours vs 15% in wild type mice)
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells
References:  24
P2Y2-deficient mice showed impaired ATP- and adenosine 5'[γ-thio] triphosphate (ATPγS)-evoked relaxation of thoracic aorta segments
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells
References:  26
P2Y2-deficient mice showed salt-resistant arterial hypertension and facillitated Na+ and water renal reabsorption
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells
References:  50
P2Y2 deficient mice showed profound deficits in UTP-evoked calcium transients in dorsal root ganglia and a potentiation of capsaicin responses. P2Y2 deficient mice were also deficient in the detection of painful heat.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells
References:  41
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
P2ry2tm1Bhk P2ry2tm1Bhk/P2ry2tm1Bhk
involves: 129P2/OlaHsd		 MGI:105107  MP:0003651 abnormal axon outgrowth PMID: 16365320 
P2ry2tm1Bhk P2ry2tm1Bhk/P2ry2tm1Bhk
involves: 129P2/OlaHsd * C57BL/6 * DBA/2		 MGI:105107  MP:0001765 abnormal ion homeostasis PMID: 10473605  10473606 
P2ry2tm1Bhk P2ry2tm1Bhk/P2ry2tm1Bhk
involves: 129P2/OlaHsd		 MGI:105107  MP:0009937 abnormal neuron differentiation PMID: 16365320 
P2ry2tm1Bhk P2ry2tm1Bhk/P2ry2tm1Bhk
involves: 129P2/OlaHsd * C57BL/6 * DBA/2		 MGI:105107  MP:0003638 abnormal response/metabolism to endogenous compounds PMID: 10473605  10473606 
P2ry2tm1Bhk P2ry2tm1Bhk/P2ry2tm1Bhk
involves: 129P2/OlaHsd		 MGI:105107  MP:0003638 abnormal response/metabolism to endogenous compounds PMID: 16365320 
Biologically Significant Variants
Three frequent nonsynonymous P2Y2 receptor polymorphisms have been identified, one of which was significantly more common in cystic fibrosis patients. This polymorphism is linked to increase in Ca2+ influx in transfected cells, and might therefore play a role in disease development or in P2Y2 agonist therapy to cystic fibrosis.
Type:  Naturally occuring mutations
Species:  Human
References:  8
General Comments
The three human transcript variants encode for the same 377 aa protein sequence [46]. P2Y2 receptors have been localized in mitochondria in rat astrocytes, C6 glioma cells and liver, suggesting their role in regulating mitochondrial calcium transport [6] [35]. Denufosol tetrasodium is currently under evaluation as an inhaled treatment for cystic fibrosis (phase III clinical study), and diquafosol is in phase III clinical study for dry eye disease (http://clinicaltrials.gov/ct2/home)

REFERENCES

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To cite this database page, please use the following:

Maria-Pia Abbracchio, Jean-Marie Boeynaems, José L. Boyer, Geoffrey Burnstock, Stefania Ceruti, Marta Fumagalli, Christian Gachet, Rebecca Hills, Robert G. Humphries, Kenneth A. Jacobson, Charles Kennedy, Brian F. King, Davide Lecca, Maria Teresa Miras-Portugal, Gary A. Weisman.
P2Y receptors: P2Y2 receptor. Last modified on 13/02/2013. Accessed on 22/05/2013. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=324.


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