The inflammatory effects of UDP-glucose in N9 microglia are not mediated by P2Y14 receptor activation

Brautigam, Vielska M.; Dubyak, George R.; Crain, Jessica M.; Watters, Jyoti J.

doi:10.1007/s11302-008-9095-1

Cited by 20 publications

(10 citation statements)

References 13 publications

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“…In murine N9 microglia cells the pro-inflammatory effect of UDPG was insensitive to PTX [24]. UDPG was able to inhibit cyclic AMP production in human astrocytoma U373 MG cells and with sensitivity to PTX, however, the P2Y 14 receptor was not detected in these cells [17].…”

Section: Discussionmentioning

confidence: 99%

UDP-glucose acting at P2Y14 receptors is a mediator of mast cell degranulation

Gao

Ding

Jacobson

2010

Biochemical Pharmacology

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UDP-glucose (UDPG), a glycosyl donor in the biosynthesis of carbohydrates, is an endogenous agonist of the G protein-coupled P2Y 14 receptor. RBL-2H3 mast cells endogenously express a P2Y 14 receptor at which UDPG mediates degranulation as indicated by β-hexosaminidase (HEX) release. Both UDPG and a more potent, selective 2-thio-modified UDPG analog, MRS2690 (diphosphoric acid 1-α-D-glucopyranosyl ester 2-(2-thiouridin-5''-yl) ester), caused a substantial calcium transient in RBL-2H3 cells, which was blocked by pertussis toxin, indicating the presence of the G i -coupled P2Y 14 receptor, supported also by quantitative detection of abundant mRNA. Expression of the closely related P2Y 6 receptor was over 100 times lower than the P2Y 14 receptor, and the P2Y 6 agonist 3-phenacyl-UDP was inactive in RBL-2H3 cells. P2Y 14 receptor agonists also induced [ 35 S]GTPγS binding to RBL-2H3 cell membranes, and phosphorylation of ERK1/2, P38 and JNK. UDPG and MRS2690 concentration-dependently enhanced HEX release with EC 50 values of 1150 ± 320 and 103 ± 18 nM, respectively. The enhancement was completely blocked by pertussis toxin and significantly diminished by P2Y 14 receptor-specific siRNA. Thus, mast cells express an endogenous P2Y 14 receptor, which mediates G i -dependent degranulation and is therefore a potential novel therapeutic target for allergic conditions.

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Section: Discussionmentioning

confidence: 99%

UDP-glucose acting at P2Y14 receptors is a mediator of mast cell degranulation

Gao

Ding

Jacobson

2010

Biochemical Pharmacology

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“…Uridine 5′-diphosphate (UDP) also has been reported to be a partial agonist/competitive antagonist at the human P2Y 14 receptor and a potent agonist at the rat P2Y 14 receptor 15. Identification of the physiological functions of the P2Y 14 receptor has been difficult to establish,16,17 in part due to a lack of selective high affinity agonists and antagonists for this receptor. The P2Y 14 receptor plays a role in the neuroimmune system, with expression occurring in T cells, dendritic cells, hematopoietic stem cells, and other tissues.…”

Section: Introductionmentioning

confidence: 99%

“…13 However, a 2-thiouracil modification in 2 (MRS2690) increased potency by 7-fold, and the corresponding 4-thio analogue 3 was equipotent to 1 . Molecular modeling of the human P2Y 14 receptor based on a rhodopsin template and ligand docking have aided in visualizing putative molecular interactions within the binding site 13,16,18. Agonist ligand docking correctly predicted potent agonism of UDP-fructose, UDP-mannose, and UDP-inositol.…”

Section: Introductionmentioning

confidence: 99%

Molecular recognition in the P2Y14 receptor: Probing the structurally permissive terminal sugar moiety of uridine-5′-diphosphoglucose

Das

Carter

et al. 2009

Bioorganic & Medicinal Chemistry

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The P2Y 14 receptor, a nucleotide signaling protein, is activated by uridine-5′-diphosphoglucose 1 and other uracil nucleotides. We have determined that the glucose moiety of 1 is the most structurally permissive region for designing analogues of this P2Y 14 agonist. For example, the carboxylate group of uridine-5′-diphosphoglucuronic acid proved to be suitable for flexible substitution by chain extension through an amide linkage. Functionalized congeners containing terminal 2-acylaminoethylamides prepared by this stratgegy retained P2Y 14 activity, and molecular modeling predicted close proximity of this chain to the 2nd extracellular loop of the receptor. In addition, replacement of glucose with other sugars did not diminish P2Y 14 potency. For example, the [5″] ribose derivative had an EC 50 of 0.24 μM. Selective monofluorination of the glucose moiety indicated a role for the 2″-and 6″-hydroxyl groups of 1 in receptor recognition. The β-glucoside was 2-fold less potent than the native α-isomer, but methylene replacement of the 1″-oxygen abolished activity. Replacement of the ribose ring system with cyclopentyl or rigid bicyclo[3.1.0]hexane groups abolished activity. Uridine-5′-diphosphoglucose also activates the P2Y 2 receptor, but the 2-thio analogue and several of the potent modified-glucose analogues were P2Y 14 -selective.

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“…It was previously suggested that P2Y 14 -mediated calcium signalling is related to P2Y 14 glycosylation since in glioma C6 cells only N-glycosylated P2Y 14 was able to induce [Ca 2+ ] i elevations [63]. Moreover, it was shown that synthetic and microbial UDPG preparations induced different responses in N9 microglial cells: 15 µM synthetic UDPG inhibited phosphorylation of cAMP response element-binding protein (CREB), thereby indicating reduced cAMP levels, while 15 µM microbial UDPG had no effect [69]. This raises the concern that microbial UDPG preparations, which are used in most P2Y 14 studies (including this study), contain contaminants that may mediate P2Y 14 -independent or mask P2Y 14 -dependent outcomes.…”

Section: P2y 14 Signal Transductionmentioning

confidence: 99%

Role of UDP-Sugar Receptor P2Y14 in Murine Osteoblasts

Mikolajewicz

Komarova

2020

IJMS

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The purinergic (P2) receptor P2Y14 is the only P2 receptor that is stimulated by uridine diphosphate (UDP)-sugars and its role in bone formation is unknown. We confirmed P2Y14 expression in primary murine osteoblasts (CB-Ob) and the C2C12-BMP2 osteoblastic cell line (C2-Ob). UDP-glucose (UDPG) had undiscernible effects on cAMP levels, however, induced dose-dependent elevations in the cytosolic free calcium concentration ([Ca2+]i) in CB-Ob, but not C2-Ob cells. To antagonize the P2Y14 function, we used the P2Y14 inhibitor PPTN or generated CRISPR-Cas9-mediated P2Y14 knockout C2-Ob clones (Y14KO). P2Y14 inhibition facilitated calcium signalling and altered basal cAMP levels in both models of osteoblasts. Importantly, P2Y14 inhibition augmented Ca2+ signalling in response to ATP, ADP and mechanical stimulation. P2Y14 knockout or inhibition reduced osteoblast proliferation and decreased ERK1/2 phosphorylation and increased AMPKα phosphorylation. During in vitro osteogenic differentiation, P2Y14 inhibition modulated the timing of osteogenic gene expression, collagen deposition, and mineralization, but did not significantly affect differentiation status by day 28. Of interest, while P2ry14-/- mice from the International Mouse Phenotyping Consortium were similar to wild-type controls in bone mineral density, their tibia length was significantly increased. We conclude that P2Y14 in osteoblasts reduces cell responsiveness to mechanical stimulation and mechanotransductive signalling and modulates osteoblast differentiation.

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The inflammatory effects of UDP-glucose in N9 microglia are not mediated by P2Y14 receptor activation

Cited by 20 publications

References 13 publications

UDP-glucose acting at P2Y14 receptors is a mediator of mast cell degranulation

UDP-glucose acting at P2Y14 receptors is a mediator of mast cell degranulation

Molecular recognition in the P2Y14 receptor: Probing the structurally permissive terminal sugar moiety of uridine-5′-diphosphoglucose

Role of UDP-Sugar Receptor P2Y14 in Murine Osteoblasts

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