Purinergic (P2Y) 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.

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 G_α and G_β/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 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 :

• IUPHAR Receptor Code

• BJP Guide

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!

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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.

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P2Y Receptor Gene Data