Purinergic GPCR Family Subtypes and Products

What Are Purinergic Receptors?

Purinergic receptors are a family of G protein-coupled receptors (GPCRs) found all throughout the body, and are involved in a variety of biological processes, such as vasodilation, blood clotting, and immune system response. Purinergic receptors have wide pharmacological utility, and are currently a large drug target. Established therapeutic uses of purinergic receptors include medication such as clopidogrel, a blood thinner, denufosol, which is used to treat cystic fibrosis, and diquafosol, used for treating dry eye disease. Research is currently being done to determine the potential of P2Y receptors in treating migraines, osteoporosis, diabetes, and heart attacks.

Purinergic Receptor Information

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G-protein coupled receptor 17 (GPR17) is closely related to the purinergic and cysteinyl-leukotriene receptor families. It is present on both neurons and a subset of oligiodendrocyte precursor cells. Recent studies have shown that GPR17 plays an important role in both sensing and repairing brain damage. Thus, GPR17 represents a potential new target for the treatment of traumatic brain injuries as well as neurodegenerative diseases like Alzheimer’s and multiple sclerosis.

P2Y1 is a receptor for ATP and ADP. P2Y1 contributes to platelet shape change. A number of P2Y1 receptor-specific antagonists, such as, MRS-2179, A3P5PS, A3P5P and A2P5P have been discovered. They inhibit calcium ion mobilization and shape change in platelets. P2Y1-deficient mice and mice treated with the P2Y1 antagonist MRS2179 displayed significantly less arterial thrombosis than their respective controls. Combination of P2Y1 deficiency with P2Y12 inhibition led to a significant additive effect.

The P2Y2 receptor was the first of this family of receptors that can be fully activated by both ATP and UTP. P2Y2 receptors are present on all of the body’s mucosal surfaces, including the lungs, eyes, upper airways, mouth, vaginal tract and gastrointestinal tract. P2Y2 receptors have also been found on non-mucosal surfaces, such as the retinal pigment epithelium. Activation of P2Y2 has been shown to stimulate mucosal hydration and mucociliary clearance in the lungs and upper airways and induce secretion of therapeutically significant amounts of fluid and tear components to the ocular surface. Thus, P2Y2 receptors are therapeutic targets for treating serious disorders including cystic fibrosis, a fatal genetic disease, retinal detachment as well as dry eye disease.

P2Y4 is a 365-amino acid 7 transmembrane protein. It has been shown that, when expressed in a mammalian cell line, the receptor protein was activated specifically by UTP and UDP, but not by ATP and ADP. Activation of P2RY4 resulted in increased inositol phosphate formation and calcium mobilization. Adrian et al, anazlyed the espression of several purinergic receptors during differentiation in a promyelocytic leukemia cell line. Granulocytic differentiation was induced by dimethylsulfoxide, and a monocytic/macrophage phenotype was induced by phorbol esters. P2RY4 was highly expressed in uninduced promyelocytes, and its expression decreased slightly following both granulocytic and monocytic differentiation.

The human P2Y6 receptor is a member of the G protein-coupled P2 receptor family that responds specifically to the extracellular nucleotide uridine diphosphate (UDP). The distribution of the P2Y6 receptor is widespread including heart, blood vessels and brain. P2Y6 receptors are significantly upregulated in T cells infiltrating regions of inflamed bowel and are involved in monocytic release of IL-8 in response to UDP or lipopolysaccharide (LPS). The immune effect of UDP/P2Y6 signaling on the production of proinflammatory cytokines has been shown to be selective and dependent on cell types.

P2Y purinoceptor 11 encodes P2Y11 (P2Y11) which is a receptor for ATP and ADP coupled to G-proteins that activate both phosphatidylinositol-calcium and adenylyl cyclase second messenger systems. P2Y11 receptor is unique amongst P2Y receptors with its coupling to the adenylyl cyclase pathway. Through this mechanism, released nucleotides can increase in P2Y11-containing cells. P2Y11 receptor has been reported to be involved in the granulocytic differentiation of promyelocytes and in the maturation of monocyte-derived dendritic cells.

P2RY12 or P2Y12 is a G-protein coupled receptor for ADP and ATP. ADT released from platelets acts in a positive feedback mechanism on P2Y12 and P2Y1 on platelets and is critical for sustained aggregation and stabilization of thrombin. P2Y12 receptor plays a central role in platelet activation and is the target of of antithrombotic drugs such as ticlopidine and clopidogrel.

GPR86 or P2Y13 is a 333-amino acid 7 transmembrane protein that lacks a leader peptide but posseses a DRF motif. Northern blot and PCR analysis has shown GPR86 to be expressed highly in the spleen, with weaker expression in placenta, leukocytes, brain, placenta, lung, liver, spinal cord, thymus, small intestine, uterus, stomach, testis, fetal brain and adrenal glad and no expression in the pancreas, heart, kidney, skeletal muscle, ovary or fetal aorta. Communi et al determined that GPR86 shows a high affinity for ADP through pharmacologic charactization of GPR86-transfected human astrocytoma cells and CHO cells.

P2Y14 (GPR105) is a purinergic G protein-coupled receptor that specifically responds to UDP-glucose and related sugar-nucleotides. This receptor has important structural similarities to known members of the P2Y receptor family but also shows a distinctly different pharmacological profile, as the receptor does not respond to ATP, ADP, UTP, UDP, other nucleotides, dinucleotides, and nucleosides. Widespread distribution of P2Y14 has been observed in humans, with highest expression in placenta, adipose tissue, stomach and intestine, and moderate levels in the brain, spleen, lung and heart. In transfected cells, the P2Y14 receptor reportedly couples to pertussis toxin-sensitive Gαi/o proteins. However, the transduction pathway(s) used by this receptor in native systems still remains to be defined.

Purinergic Cell Lines

Receptor FamilyReceptorSpeciesParentalStable Cell Lines Division-Arrested Cells Membranes
PurinergicGPR17 (long form)human1321N1C1076-3DC1076-3MC1076-3
GPR17 (long form)human1321N1C1076-3aDC1076-3aMC1076-3a
GPR17 (short form)human1321N1C1526-3DC1526-3MC1526-3
P2Y12ratCHO dhfr-C1170-1DC1170-1MC1170-1
P2Y14humanHEK293T Gαqi5CG1057DCG1057MCG1057
P2Y14ratHEK293T Gαqi5CGr1057DCGr1057MCGr1057
P2Y14monkeyHEK293T Gαqi5CGp1057DCGp1057MCGp1057