Purinergic (P2Y) Receptors

P2Y purinergic receptors are G protein-coupled receptors (GPCRs) that are activated by extracellular adenine and uridine nucleotides such as ATP, ADP and UTP. The related ligand-gated ion channels, P2X receptors, are only activated by ATP. There are 8 mammalian P2Y receptors that signal through a wide range of intracellular effectors, including heterotrimeric G proteins, β-arrestins, MAPK and ERK pathways, direct and indirect regulation of ion channels, and receptor and non-receptor kinases. These receptors are found in most human tissues and have diverse physiological roles.

Products
Background
Literature (5)
Gene Data

Agonists

Cat. No. Product Name / Activity
3245 ATP disodium salt
P2 agonist
4080 ATPγS tetralithium salt
Non-selective P2 agonist; analog of ATP (Cat. No. 3245)
3312 BzATP triethylammonium salt
P2Y1 partial agonist. Also P2X7 agonist and P2X1 partial agonist
3209 α,β-Methyleneadenosine 5'-triphosphate trisodium salt
Non-selective P2 agonist
1624 2-Methylthioadenosine diphosphate trisodium salt
Potent agonist at P2Y1, P2Y12 and P2Y13
1062 2-Methylthioadenosine triphosphate tetrasodium salt
Non-selective P2 agonist
2157 MRS 2365
Highly potent and selective P2Y1 agonist
2915 MRS 2690
Potent P2Y14 agonist
2502 MRS 2693 trisodium salt
Selective P2Y6 agonist
3884 MRS 2768 tetrasodium salt
Selective P2Y2 agonist
5633 MRS 2905
Potent and selective P2Y14 receptor agonist
4260 MRS 2957 triethylammonium salt
Potent and selective P2Y6 agonist
4261 MRS 4062 triethylammonium salt
Selective P2Y4 receptor agonist
3892 NF 546
Selective P2Y11 agonist
4376 5-OMe-UDP trisodium salt
Potent P2Y6 agonist
2715 PSB 0474
Potent and selective P2Y6 agonist
4333 PSB 1114
Potent, selective P2Y2 agonist
3280 2-ThioUTP tetrasodium salt
Potent and selective P2Y2 agonist
3279 UTPγS trisodium salt
Selective P2Y2/4 agonist

Antagonists

Cat. No. Product Name / Activity
4890 AR-C 118925XX
Selective and competitive P2Y2 antagonist
3321 AR-C 66096 tetrasodium salt
Potent and selective P2Y12 antagonist
5720 AR-C 69931 tetrasodium salt
Highly potent P2Y12 antagonist
6085 AZD 1283
High affinity P2Y12 antagonist
1820 (+)-Clopidogrel hydrogen sulfate
Selective P2Y12 antagonist
2490 (±)-Clopidogrel hydrochloride
Selective P2Y12 antagonist
5316 Elinogrel
P2Y12 antagonist
0900 MRS 2179 tetrasodium salt
Selective P2Y1 antagonist
2402 MRS 2211
Competitive P2Y13 antagonist
2158 MRS 2279
Selective, high affinity P2Y1 antagonist
2159 MRS 2500 tetraammonium salt
Highly potent and selective P2Y1 antagonist
2146 MRS 2578
Selective P2Y6 antagonist
2450 NF 157
Selective P2Y11/P2X1 antagonist
0625 PPADS tetrasodium salt
Non-selective P2 antagonist
4862 PPTN hydrochloride
High affinity and selective P2Y14 antagonist
6317 Prasugrel
Irreversible P2Y12 antagonist; antiplatelet and orally active
3983 PSB 0739
Highly potent P2Y12 antagonist
5650 SAR 216471 hydrochloride
Potent P2Y12 antagonist; orally available
6864 Ticagrelor
High affinity and reversible P2Y12 antagonist; displays inverse agonism in vitro; also inhibits ENT1

Modulators

Cat. No. Product Name / Activity
6078 BPTU
P2Y1 allosteric antagonist

Other

Cat. No. Product Name / Activity
5157 DMNPE-caged ATP diammonium salt
Caged ATP
1682 PIT
P2Y ligand; displays mixed antagonism/potentiation
3111 UDP disodium salt
Endogenous ligand; competitive antagonist at P2Y14 receptors

P2Y Purinergic Receptor Family

The P2Y purinergic receptor family consists of 8 mammalian receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13 and P2Y14), as well as the non-mammalian chick p2y3, Xenopus p2y8 and turkey p2y receptors. The p2y9 and p2y10 receptors are orphan receptors, and p2y5 was found to be a leukotriene B4 receptor. The mammalian P2Y receptors bind adenine and/or uridine nucleotides, with each receptor having a unique binding profile.

P2Y receptors are GPCRs that have 7 transmembrane domains forming the ligand binding pocket of the receptor, an extracellular N-terminus containing several potential sites for glycosylation, 3 intracellular loops that couple to heterotrimeric G proteins, and an intracellular C-terminus containing binding/phosphorylation sites for protein kinases. Although they have a conserved structure, the amino acid sequence and receptor pharmacology of P2Y receptors are highly diverse.

Human homomeric P2Y<sub>1</sub> receptor  protein structure

Figure 1: Structure of human P2Y1 receptor showing 7 transmembrane domains and intracellular domains for binding G proteins and protein kinases. Structure from Protein Data Bank. PDBID: 4XNV. Zhang et al (2015) Two disparate ligand-binding sites in the human P2Y1 receptor. Nature 520: 317-321.

Like other GPCRs, P2Y receptors function as guanine exchange factors (GEFs) for heterotrimeric G proteins. Activation of the receptor causes the dissociation of the G protein from the receptor, as well as the dissociation of the Gα and Gβ/γ subunits. Following dissociation, these G protein subunits act as effectors to engage various signaling pathways. P2Y receptors can be broadly split into two groups based on the coupled G protein, however many receptors also link to other G protein subfamilies (see table below). P2Y receptors may also activate alternative intracellular signaling pathways though β-arrestins and subsequent activation of MAPK and MEK signaling, direct and indirect modulation of ion channel activity, and receptor and non-receptor kinases.

Table 1: P2Y Receptor Signaling and Ligand Preference

P2Y Receptor G Protein Coupling & Effectors Ligands Ligand Preference
P2Y1 Gq - PLC-β, Rac, Rho activation Adenine nucleotides ADP > ATP
P2Y2 Gq - PLC-β activation
G12 - Rho activation
Adenine and uridine nucleotides ATP = UTP
P2Y4 Gq or Go - PLC-β activation Uridine triphosphates UTP > ATP
P2Y6 Gq - PLC-β activation
G12/13 - Rho activation
Uridine diphosphates UDP
P2Y11 Gq - PLC-β activation
Gs - AC activation
Adenine nucleotides ATP > ADP
P2Y12 Gi - AC inhibition, PLC-β & RhoA activation Adenine diphosphates 2-MeSADP >> ADP
P2Y13 Gi - AC inhibition, PLC-β & RhoA activation Adenine diphosphates Unknown (assay dependent)
P2Y14 Gi - AC inhibition, PLC-β & RhoA activation UDP-glucose -
AC = Adenylyl cyclases; PLC-β = Phospholipase C β

P2Y Receptor Distribution & Physiology

P2Y receptors are found in most human tissues. They have diverse physiological roles including regulation of platelet aggregation, muscle contraction, neurotransmission, and epithelial cell communication and migration. For example, P2Y6 receptors play a role in cerebral vasodilation, and are under investigation as a drug target to treat migraines, and P2Y11 receptors are thought to be a regulator of immune response.

In the nervous system, adenine nucleotides modulate neuronal activity and neuron fiber outgrowth through the activation of P2Y1 receptors on neurons. They also control the migration of microglia, a key cell type in neurodevelopment and synaptic transmission and plasticity.

P2Y receptors and platelets

The only clinically available drugs that act on P2Y receptors are P2Y12 antagonists such as prasugrel (Cat. No. 6317) and ticagrelor (Cat. No. 6864), which are antiplatelet medications. ADP acting at P2Y12 receptors on platelets induces aggregation. P2Y12 antagonists are used in the prevention and treatment of cardiovascular events.

External sources of pharmacological information for Purinergic (P2Y) Receptors :

Literature for Purinergic (P2Y) Receptors

Tocris offers the following scientific literature for Purinergic (P2Y) Receptors to showcase our products. We invite you to request* your copy today!

*Please note that Tocris will only send literature to established scientific business / institute addresses.


Cardiovascular

Cardiovascular Research Product Guide

A collection of over 250 products for cardiovascular research, the guide includes research tools for the study of:

  • Hypertension
  • Thrombosis and Hemostasis
  • Atherosclerosis
  • Myocardial Infarction
  • Ischemia/Reperfusion Injury
  • Arrhythmias
  • Heart Failure
GPCR

GPCR Product Listing

A collection of over 450 products for G protein-coupled receptors, the listing includes research tools for the study of:

  • Rhodopsin-like Receptors
  • Glutamate Receptors
  • Frizzled Receptors
  • GPCR Signaling
Pain

Pain Research Product Guide

A collection of over 280 products for pain research, the guide includes research tools for the study of:

  • Nociception
  • Ion Channels
  • G-Protein-Coupled Receptors
  • Intracellular Signaling
P2X and P2Y Receptors

P2X and P2Y Receptors Scientific Review

Written by Kenneth Jacobson, this review provides an overview of the different subtypes and structures of the P2 receptor families, as well as the pharmacological probes used to study them; compounds available from Tocris are listed.

Cardiovascular

Cardiovascular Poster

Cardiovascular disease remains one of the major causes of morbidity and mortality in the Western world and therefore this therapeutic area continues to be of great interest to researchers. This poster highlights the key GPCRs regulating vascular reactivity.

P2Y Receptor Gene Data

Gene Species Gene Symbol Gene Accession No. Protein Accession No.
P2Y1 Human P2RY1 NM_002563 P47900
Mouse P2ry1 NM_008772 P49650
Rat P2ry1 NM_012800 P49651
P2Y2 Human P2RY2 NM_176072 P41231
Mouse Pyry2 NM_008773 P35383
Rat P2ry2 NM_017255 P41232
P2Y4 Human P2RY4 NM_002565 P51582
Mouse P2ry4 NM_020621 Q9JJS7
Rat P2ry4 NM_031680 O35811
P2Y6 Human P2RY6 NM_176798 Q15077
Mouse P2ry6 NM_183168 Q9ERK9
Rat P2ry6 NM_057124 Q63371
P2Y11 Human P2RY11 NM_002566 Q96G91
P2Y12 Human P2RY12 NM_022788 Q9H244
Mouse P2ry12 NM_027571 Q9CPV9
Rat P2ry12 NM_022800 Q9EPX4
P2Y13 Human P2RY13 NM_023914 Q9BPV8
Mouse P2ry13 NM_028808 Q9D8I2
Rat P2ry13 NM_001002853 Q6GUG4
P2Y14 Human P2RY14 NM_014879 Q15391
Mouse P2ry14 NM_133200 Q9ESG6
Rat P2ry14 NM_133577 O35881