Tools and drugs for uracil nucleotide-activated P2Y receptors

Rafehi, Muhammad; Müller, Christa E.

doi:10.1016/j.pharmthera.2018.04.002

Cited by 52 publications

(41 citation statements)

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“…P2Y receptors are activated by mononucleotides such as ADP ( 1 ), ATP ( 2 ), UDP ( 3 ), or UTP ( 4 ), by dinucleotides like diadenosine tetraphosphate (Ap 4 A, 5 ) or diuridine tetraphosphate (Up 4 U, 6 ), and/or by nucleotide sugars such as uridine 5′‐diphosphoglucose (UDP‐glucose, 7 ; see Figure 1). Selective agonists and antagonists are important for studying the roles of P2Y receptor subtypes in physiology and pathophysiology (Figures 1 and 2, Table 1, Abbracchio et al, 2019; Conroy, Kindon, Kellam, & Stocks, 2016; Jacobson & Müller, 2016; Rafehi & Müller, 2018). Their structure–activity relationship at each P2Y receptor subtype has been developed in detail through chemical efforts.…”

Section: Selective Ligand Tools To Study P2y Receptorsmentioning

confidence: 99%

“…The G q ‐coupled P2Y 6 receptor prefers UDP as an agonist (Abbracchio et al, 2006, 2019). Analogues including 3‐phenacyl‐UDP (PSB‐0474, 20 ; El‐Tayeb et al, 2011), 5‐iodo‐UDP (MRS2693, 21 ; Ko et al, 2008), α,β‐methylene‐UDP (MRS2782, 22 ; Ko et al, 2008), INS48823 ( 23 , Korcok, Raimundo, Du, Sims, & Dixon, 2005; Rafehi & Müller, 2018), and 5‐methoxy‐UDP ( 24 , Ginsburg‐Shmuel et al, 2012) are much more potent agonists.…”

Section: Selective Ligand Tools To Study P2y Receptorsmentioning

confidence: 99%

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Update of P2Y receptor pharmacology: IUPHAR Review 27

Jacobson

Delicado

Gachet

et al. 2020

British J Pharmacology

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Eight G protein-coupled P2Y receptor subtypes respond to extracellular adenine and uracil mononucleotides and dinucleotides. P2Y receptors belong to the δ group of rhodopsin-like GPCRs and contain two structurally distinct subfamilies: P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 , and P2Y 11 (principally G q protein-coupled P2Y 1 -like) and P2Y 12-14 (principally G i protein-coupled P2Y 12 -like) receptors. Brain P2Y receptors occur in neurons, glial cells, and vasculature. Endothelial P2Y 1 , P2Y 2 , P2Y 4 , and P2Y 6 receptors induce vasodilation, while smooth muscle P2Y 2 , P2Y 4 , and P2Y 6 receptor activation leads to vasoconstriction. Pancreatic P2Y 1 and P2Y 6 receptors stimulate while P2Y 13 receptors inhibits insulin secretion. Antagonists of P2Y 12 receptors, and potentially P2Y 1 receptors, are anti-thrombotic agents, and a P2Y 2 /P2Y 4 receptor agonist treats dry eye syndrome in Asia. P2Y receptor agonists are generally pro-inflammatory, and antagonists may eventually treat inflammatory conditions. This article reviews recent developments in P2Y receptor pharmacology (using synthetic agonists and antagonists), structure and biophysical properties (using X-ray crystallography, mutagenesis and modelling), physiological and pathophysiological roles, and present and potentially future therapeutic targeting.Abbreviations: BMD, bone mineral density; DUSP, dual specificity protein phosphatase; ECL, extracellular loop; EPAC, exchange protein activated by cAMP; KO, knockout; MSD, musculoskeletal disorder; SNP, single nucleotide polymorphism; SS, Sjögren's syndrome; TM, transmembrane helix.

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Section: Selective Ligand Tools To Study P2y Receptorsmentioning

confidence: 99%

Section: Selective Ligand Tools To Study P2y Receptorsmentioning

confidence: 99%

Update of P2Y receptor pharmacology: IUPHAR Review 27

Jacobson

Delicado

Gachet

et al. 2020

British J Pharmacology

Self Cite

180

184

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“…This is important, as the endogenous P2Y agonists have complex pharmacological profiles and each stimulates at least two of the eight subtypes. UTP activates not only P2Y 2 but also P2Y 4 and possibly P2Y 6 receptors (Abbracchio et al, 2006;Bar et al, 2008;Guns et al, 2006;Haanes et al, 2016;Kennedy et al, 2013;Rafehi & Müller, 2018), so sensitivity of a cell or tissue to UTP is not proof of P2Y 2 receptor expression. Furthermore, no P2Y 4 antagonists are currently commercially available, and while the P2Y 6 antagonist, MRS2578, has reasonably high potency, its action is nonsurmountable and irreversible (Mamedova, Joshi, Gao, Von Kügelgen, & Jacobson, 2004) and effects at sites other than P2Y 6 receptors have been noted (Mitchell, Syed, Tengah, Gurney, & Kennedy, 2012).…”

Section: Selectivity Of Ar-c118925xxmentioning

confidence: 99%

“…P2Y receptors are a family of eight GPCRs that mediate the actions of the endogenous nucleotides, ATP, ADP, UTP, and UDP (Abbracchio et al, ; Kennedy, Chootip, Mitchell, Syed, & Tengah, ; Rafehi & Müller, ). They are expressed in cells and tissues throughout the body, but their physiological functions are largely unclear.…”

Section: Introductionmentioning

confidence: 99%

“…AR-C118925XX was developed by AstraZeneca around 20 years ago as a P2Y 2 antagonist, but only a conference abstract was published at the time (Meghani, 2002), which did not include crucial pharmacological properties, such as its K B or pA 2 . Several studies have since been published that used AR-C118925XX to investigate the role of native P2Y 2 receptors in the actions of P2Y agonists in various cell types (Cosentino et al, 2012;Gabl et al, 2016;Hochhauser et al, 2013;Kemp, Sugar, & Jackson, 2004;Magni, Merli, Verderio, Abbracchio, & Ceruti, 2015;Onnheim et al, 2014;Wang et al, 2015; see also review by Rafehi & Müller, 2018). They did not, however, report the K B or pA 2 of AR-C118925XX or relate the concentrations used (mostly 1 and 10 μM) to its potency or selectivity.…”

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confidence: 99%

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Characterisation of P2Y₂ receptors in human vascular endothelial cells using AR‐C118925XX, a competitive and selective P2Y₂ antagonist

Muoboghare

Drummond

Kennedy

2019

British J Pharmacology

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Background and Purpose There is a lack of potent, selective antagonists at most subtypes of P2Y receptor. The aims of this study were to characterise the pharmacological properties of the proposed P2Y2 receptor antagonist, AR‐C118925XX, and then to use it to determine the role of P2Y2 receptors in the action of the P2Y2 agonist, UTP, in human vascular endothelial cells. Experimental Approach Cell lines expressing native or recombinant P2Y receptors were superfused constantly, and agonist‐induced changes in intracellular Ca2+ levels monitored using the Ca2+‐sensitive fluorescent indicator, Cal‐520. This set‐up enabled full agonist concentration–response curves to be constructed on a single population of cells. Key Results UTP evoked a concentration‐dependent rise in intracellular Ca2+ in 1321N1‐hP2Y2 cells. AR‐C118925XX (10 nM to 1 μM) had no effect per se on intracellular Ca2+ but shifted the UTP concentration–response curve progressively rightwards, with no change in maximum. The inhibition was fully reversible on washout. AR‐C118925XX (1 μM) had no effect at native or recombinant hP2Y1, hP2Y4, rP2Y6, or hP2Y11 receptors. Finally, in EAhy926 immortalised human vascular endothelial cells, AR‐C118925XX (30 nM) shifted the UTP concentration–response curve rightwards, with no decrease in maximum. Conclusions and Implications AR‐C118925XX is a potent, selective and reversible, competitive P2Y2 receptor antagonist, which inhibited responses mediated by endogenous P2Y2 receptors in human vascular endothelial cells. As the only P2Y2‐selective antagonist currently available, it will greatly enhance our ability to identify the functions of native P2Y2 receptors and their contribution to disease and dysfunction.

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Purinergic signaling in peripheral nervous system glial cells

Cram

Coover

Jankowski

et al. 2021

Glia

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To facilitate analyses of purinergic signaling in peripheral nerve glia, we review recent literature and catalog purinergic receptor mRNA expression in cultured mouse Schwann cells (SCs). Purinergic signaling can decrease developmental SC proliferation, and promote SC differentiation. The purinergic receptors P2RY2 and P2RX7 are implicated in nerve development and in the ratio of Remak SCs to myelinating SCs in differentiated peripheral nerve. P2RY2, P2RX7, and other receptors are also implicated in peripheral neuropathies and SC tumors. In SC tumors lacking the tumor suppressor NF1, the SC pathway that suppresses SC growth through P2RY2‐driven β‐arrestin‐mediated AKT signaling is aberrant. SC‐released purinergic agonists acting through SC and/or neuronal purinergic receptors activate pain responses. In all these settings, purinergic receptor activation can result in calcium‐independent and calcium‐dependent release of SC ATP and UDP, growth factors, and cytokines that may contribute to disease and nerve repair. Thus, current research suggests that purinergic agonists and/or antagonists might have the potential to modulate peripheral glia function in development and in disease.

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Tools and drugs for uracil nucleotide-activated P2Y receptors

Cited by 52 publications

References 304 publications

Update of P2Y receptor pharmacology: IUPHAR Review 27

Update of P2Y receptor pharmacology: IUPHAR Review 27

Characterisation of P2Y₂ receptors in human vascular endothelial cells using AR‐C118925XX, a competitive and selective P2Y₂ antagonist

Purinergic signaling in peripheral nervous system glial cells

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Tools and drugs for uracil nucleotide-activated P2Y receptors

Cited by 52 publications

References 304 publications

Update of P2Y receptor pharmacology: IUPHAR Review 27

Update of P2Y receptor pharmacology: IUPHAR Review 27

Characterisation of P2Y2 receptors in human vascular endothelial cells using AR‐C118925XX, a competitive and selective P2Y2 antagonist

Purinergic signaling in peripheral nervous system glial cells

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Characterisation of P2Y₂ receptors in human vascular endothelial cells using AR‐C118925XX, a competitive and selective P2Y₂ antagonist