A G Protein-coupled Receptor for UDP-glucose

Chambers, Jon; Macdonald, Lynn E.; Sarau, Henry M.; Ames, Robert S.; Freeman, Katie B.; Foley, James J.; Zhu, Yuan; McLaughlin, Megan M.; Murdock, Paul R.; McMillan, Lynette J.; Trill, John J.; Swift, Ann; Aiyar, Nambi; Taylor, Paul B.; Vawter, Lisa; Naheed, Sajda; Szekeres, Philip G.; Hervieu, Guillaume; Scott, Claire M.; Watson, Jeanette; Murphy, Andrew; Duzic, Emir; Klein, Christine; Bergsma, Derk J.; Wilson, Shelagh; Livi, George P.

doi:10.1074/jbc.275.15.10767

Cited by 318 publications

(307 citation statements)

References 23 publications

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“…On a speculative basis, UDP-Nacetylglucosamine and potentially UDP-galactose and UDPglucuronic acid may contribute to P2Y 14 R-dependent lung phenotypes. However, given the low P2Y 14 R agonist potency exhibited by these UDP-sugars, relative to UDP-glucose [13,54], UDP-glucose predictably is the most important autocrine/ paracrine regulator of P2Y 14 R-mediated lung inflammation. Recent studies examining P2Y 14 R-dependent second messenger formation in model cell lines revealed that UDP is a very potent agonist of this receptor [15].…”

Section: Discussionmentioning

confidence: 99%

“…The P2Y 14 R is a Gi-coupled receptor that is activated by UDP-sugars with a relative potency order of UDP-glucose > UDP-galactose > UDP-glucuronic acid > UDP-Nacetylglucosamine [13,14]. UDP also is an agonist of this receptor, but ATP, UTP, or other naturally occurring nucleoside 5′-di-or triphosphates have no P2Y 14 R activity [13][14][15][16].…”

Section: Introductionmentioning

confidence: 99%

“…UDP also is an agonist of this receptor, but ATP, UTP, or other naturally occurring nucleoside 5′-di-or triphosphates have no P2Y 14 R activity [13][14][15][16]. P2Y 14 R mRNA expression has been reported in the brain and several peripheral tissues [13], including the lung, circulating neutrophils, and other immune/inflammatory cells [17][18][19][20][21].…”

Section: Introductionmentioning

confidence: 99%

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UDP-glucose promotes neutrophil recruitment in the lung

Sesma

Weitzer

Livraghi‐Butrico

et al. 2016

Purinergic Signalling

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In addition to their role in glycosylation reactions, UDP-sugars are released from cells and activate widely distributed cell surface P2Y 14 receptors (P2Y 14 R). However, the physiological/pathophysiological consequences of UDPsugar release are incompletely defined. Here, we report that UDP-glucose levels are abnormally elevated in lung secretions from patients with cystic fibrosis (CF) as well as in a mouse model of CF-like disease, the βENaC transgenic (Tg) mouse. Instillation of UDP-glucose into wild-type mouse tracheas resulted in enhanced neutrophil lung recruitment, and this effect was nearly abolished when UDP-glucose was coinstilled with the P2Y 14 R antagonist PPTN [4-(piperidin-4-yl)-phenyl)-7-(4-(trifluoromethyl)-phenyl-2-naphthoic acid]. Importantly, administration of PPTN to βENaC-Tg mice reduced neutrophil lung inflammation. These results suggest that UDP-glucose released into the airways acts as a local mediator of neutrophil inflammation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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UDP-glucose promotes neutrophil recruitment in the lung

Sesma

Weitzer

Livraghi‐Butrico

et al. 2016

Purinergic Signalling

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“…Accordingly, it has been shown that reducing the cellular level of UDP-GlcNAc to 5% of the normal level did not affect the synthesis or secretion of N-linked glycoproteins (58). Moreover, a G protein-coupled specific cell surface receptor for UDP-Glc, P2Y 14 , was recently identified (59,60), and the release of small amounts of UDP-Glc from a variety of cultured cells into the medium was demonstrated (61). UDP-Glc was postulated as a novel autocrine and paracrine signaling molecule, although the physiological processes regulated by its widely distributed receptor remain to be clarified.…”

Section: Fig 6 a Cellular Udp-glc Deficiency Does Not Cause Xbp-1 Amentioning

confidence: 99%

A Cellular UDP-glucose Deficiency Causes Overexpression of Glucose/Oxygen-regulated Proteins Independent of the Endoplasmic Reticulum Stress Elements

Flores-Dı́az

Higuita

Florin

et al. 2004

Journal of Biological Chemistry

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A low level of UDP-Glc occurs in cells exposed to hypoxia or glucose starvation. This work reveals that a 65% reduction in the cellular UDP-Glc level causes upregulation of the mitochondrial chaperone GRP75 and the endoplasmic reticulum (ER) resident chaperones GRP58, ERp72, GRP78, GRP94, GRP170, and calreticulin. Conditions that cause misfolding of proteins within the ER activate the transcription factors ATF6␣/␤ and induce translation of the transcription factors XBP-1/ TREB5 and ATF4/CREB2. These transcription factors induce the overexpression of ER chaperones and CHOP/ GADD153. However, the 65% decrease in the cellular UDP-Glc level does not cause activation of ATF6␣, splicing of XBP-1/TREB5, induction of ATF4/CREB2, or expression of CHOP/GADD153. The activity of the promoters of the ER chaperones is increased in UDP-Glcdeficient cells, but the activity of the CHOP/GADD153 promoter is not affected, in comparison with their respective activities in cells having compensated for the UDP-Glc deficiency. The results demonstrate that the unfolded protein response remains functionally intact in cells with a 65% decrease in the cellular UDP-Glc level and provide evidence that this decrease is a stress signal in mammalian cells, which triggers the coordinate overexpression of mitochondrial and ER chaperones, independently of the ER stress elements.

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“…The most recently identified subtypes are the P2Y 13 receptor, which is present in human monocytes and lymphocytes, 42 and the P2Y 14 receptor, which is activated by UDP-glucose. 43 P2Y receptor ligands are being investigated for therapeutic applications in the cardiovascular, endocrine, and other systems. Exploration of selective agonists and antagonists modulators is most advanced at the P2Y 1 and P2Y 12 receptors, but at most of the P2Y receptors selective pharmacological probes are lacking.…”

Section: Discussionmentioning

confidence: 99%

Design and synthesis of new bicyclic diketopiperazines as scaffolds for receptor probes of structurally diverse functionality

et al. 2005

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Diketopiperazines (DKPs) are a common motif in various biologically active natural products, and hence they may be useful scaffolds for the rational design of receptor probes and therapeutic agents. We constructed a new bicyclic scaffold that combines a DKP bridged with a 10-membered ring. In this way we obtained a three-dimensional molecular skeleton, with several amendable sites that provide a starting point to design a new combinatorial library having diverse substituent groups. Structural variation is based upon the flexibility of alkylation of the nitrogen atoms of the DKP and on the side-chain olefin. We obtained a 10-membered secondary ring through a ringclosure metathesis reaction using the second generation Grubbs catalyst. Rings containing both Oethers and S-ethers were compared. N-Alkyl or arylalkyl groups were introduced optionally at the two Nα-atoms. This is a general scheme that will allow us to test rings of varying sizes, linkages, and stereochemical parameters. The DKP derivatives were tested for activity in astrocytoma cells expressing receptors coupled to phospholipase C. Inhibitory effects were observed for signaling elicited by activation of human nucleotide P2Y receptors but not m3 muscarinic receptors. Compound 20 selectively inhibited calcium mobilization (IC 50 value of 486 ± 16 nM) and phosphoinositide turnover elicited by a selective P2Y 1 receptor agonist, but this compound did not compete for binding of a radiolabeled nucleotide-competitive receptor antagonist. Therefore, the new class of DKP derivatives shows utility as pharmacological tools for P2Y receptors.

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A G Protein-coupled Receptor for UDP-glucose

Cited by 318 publications

References 23 publications

UDP-glucose promotes neutrophil recruitment in the lung

UDP-glucose promotes neutrophil recruitment in the lung

A Cellular UDP-glucose Deficiency Causes Overexpression of Glucose/Oxygen-regulated Proteins Independent of the Endoplasmic Reticulum Stress Elements

Design and synthesis of new bicyclic diketopiperazines as scaffolds for receptor probes of structurally diverse functionality

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