P2X and P2Y Nucleotide Receptors as Targets in Cardiovascular Disease

Kennedy, Charles; Chootip, Krongkarn; Mitchell, Callum; Syed, Nawazish-i-Husain; Tengah, Asrin

doi:10.4155/fmc.13.6

Cited by 23 publications

(26 citation statements)

References 146 publications

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“…In both studies, one group of agonists caused the cytoplasmic end of helix VI of the receptor to move, shifting the equilibrium towards G protein coupling, whilst another group moved the cytoplasmic end of helix VII, leading to binding of β-arrestin to the receptor. P2Y receptors are activated by endogenous nucleotides, such as adenosine 5′-triphosphate (ATP) and uridine 5′-triphosphate (UTP) [6][7][8], but there are few reports of biased agonism. ATP and UTP induce differential interaction of the human P2Y 2 receptor with β-arrestins and the downstream increase in phosphorylation of ERK elicited by UTP was transient, whereas the response to ATP was prolonged [9].…”

Section: Introductionmentioning

confidence: 99%

UTP is not a biased agonist at human P2Y11 receptors

Morrow

Nicholas

Kennedy

2014

Purinergic Signalling

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Biased agonism describes a multistate model of G protein-coupled receptor activation in which each ligand induces a unique structural conformation of the receptor, such that the receptor couples differentially to G proteins and other intracellular proteins. P2Y receptors are G protein-coupled receptors that are activated by endogenous nucleotides, such as adenosine 5′-triphosphate (ATP) and uridine 5′-triphosphate (UTP). A previous report suggested that UTP may be a biased agonist at the human P2Y 11 receptor, as it increased cytosolic [Ca 2+ ], but did not induce accumulation of inositol phosphates, whereas ATP did both. The mechanism of action of UTP was unclear, so the aim of this study was to characterise the interaction of UTP with the P2Y 11 receptor in greater detail. Intracellular Ca 2+ was monitored in 1321N1 cells stably expressing human P2Y 11 receptors using the Ca 2+ -sensitive fluorescent indicator, fluo-4. ATP evoked a rapid, concentration-dependent rise in intracellular Ca 2+ , but surprisingly, even high concentrations of UTP were ineffective. In contrast, UTP was slightly, but significantly more potent than ATP in evoking a rise in intracellular Ca 2+ in 1321N1 cells stably expressing the human P2Y 2 receptor, with no difference in the maximum response. Thus, the lack of response to UTP at hP2Y 11 receptors was not due to a problem with the UTP solution. Furthermore, coapplying a high concentration of UTP with ATP did not inhibit the response to ATP. Thus, contrary to a previous report, we find no evidence for an agonist action of UTP at the human P2Y 11 receptor, nor does UTP act as an antagonist.

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Section: Introductionmentioning

confidence: 99%

UTP is not a biased agonist at human P2Y11 receptors

Morrow

Nicholas

Kennedy

2014

Purinergic Signalling

Self Cite

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“…For example, we found a highly significant down-regulation of the beta 1 adrenergic receptor (ADRB1) in 19/21 groups, which is well known for its crucial role in heart function and down-regulation in heart failure [36-38]. Other interesting candidates for in depth analysis were predicted, like P2Y receptor subunits, a receptor class expressed in various heart cells and regulating cardiovascular function in health and disease [39-46]. We also found a high significance for sphingosine-1-phospate receptor 3 (S1PR3) being down-regulated in 14/14 groups.…”

Section: Resultsmentioning

confidence: 99%

Array data extractor (ADE): a LabVIEW program to extract and merge gene array data

Kurtenbach

Zoidl

2013

BMC Res Notes

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BackgroundLarge data sets from gene expression array studies are publicly available offering information highly valuable for research across many disciplines ranging from fundamental to clinical research. Highly advanced bioinformatics tools have been made available to researchers, but a demand for user-friendly software allowing researchers to quickly extract expression information for multiple genes from multiple studies persists.FindingsHere, we present a user-friendly LabVIEW program to automatically extract gene expression data for a list of genes from multiple normalized microarray datasets. Functionality was tested for 288 class A G protein-coupled receptors (GPCRs) and expression data from 12 studies comparing normal and diseased human hearts. Results confirmed known regulation of a beta 1 adrenergic receptor and further indicate novel research targets.ConclusionsAlthough existing software allows for complex data analyses, the LabVIEW based program presented here, “Array Data Extractor (ADE)”, provides users with a tool to retrieve meaningful information from multiple normalized gene expression datasets in a fast and easy way. Further, the graphical programming language used in LabVIEW allows applying changes to the program without the need of advanced programming knowledge.

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“…P2Y receptors have been heavily investigated in the context of thrombosis and heart disease, and P2X receptors have been studied in the context of inflammatory and psychological disorders and in bone homeostasis. This is an exciting time in the nucleotide receptor field as there is growing interest in the potential translational possibilities of exploiting the P2X and P2Y receptors (Lenertz et al, 2011; Barn and Steinhubl, 2012; Kennedy et al, 2013). …”

Section: Nucleotide Receptor Overviewmentioning

confidence: 99%

Control of bone development by P2X and P2Y receptors expressed in mesenchymal and hematopoietic cells.

Lenertz

Baughman

Waldschmidt

et al. 2015

Gene

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Bone development and homeostasis require the interplay between several cell types, including mesenchymal osteoblasts and osteocytes, as well as hematopoietic osteoclasts. Recent evidence suggests that cell proliferation, differentiation and apoptosis of both mesenchymal and hematopoietic stem cells, which are fundamental for tissue regeneration and treatment of degenerative diseases, is controlled by P2 receptors (i.e., P2X and P2Y receptors). Both types of P2 receptors are versatile transducers of diverse signals activated by extracellular nucleotides like ATP that are released in response to tissue injury, infection or shear stress. The P2X family of receptors has been shown to mediate multiple signaling events including the influx of calcium, activation of mitogen activated protein kinases (MAPKs) and induction of AP-1 family members known to regulate bone development. Support for the significance of P2X7 in regulating bone development and homeostasis has been provided by several studies focusing on animal models and single nucleotide polymorphisms. P2 receptors are functionally expressed in both bone forming osteoblasts and bone resorbing osteoclasts, while recent findings also suggest that these receptors translate mechanical stimuli in osteocytes. Their ability to respond to external nucleotide analogs renders these cell surface proteins excellent targets for skeletal regenerative therapies. This overview summarizes mechanisms by which nucleotide receptors control skeletal cells and contribute to bone tissue development remodeling and repair.

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P2X and P2Y Nucleotide Receptors as Targets in Cardiovascular Disease

Cited by 23 publications

References 146 publications

UTP is not a biased agonist at human P2Y11 receptors

UTP is not a biased agonist at human P2Y11 receptors

Array data extractor (ADE): a LabVIEW program to extract and merge gene array data

Control of bone development by P2X and P2Y receptors expressed in mesenchymal and hematopoietic cells.

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