GPR105, a novel Gi/o-coupled UDP-glucose receptor expressed on brain glia and peripheral immune cells, is regulated by immunologic challenge: possible role in neuroimmune function

Moore, Darren J.; Murdock, Paul R.; Watson, Jeannette M.; Faull, Richard L.M.; Waldvogel, Henry J.; Szekeres, Philip G.; Wilson, Shelagh; Freeman, Katie B.; Emson, Piers C.

doi:10.1016/s0169-328x(03)00330-9

Cited by 89 publications

(90 citation statements)

References 45 publications

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“…Although the function of P2Y14 in any cell type remains unclear, in immature dendritic cells, activation of P2Y14 receptors increases expression of CD86, suggesting their involvement in dendritic cell maturation [13]. Also, proinflammatory stimuli such as LPS [8] and interferon-γ (JMC and JJW, unpublished observations) increase the expression levels of GPR105 in glial cells and in N9 microglia, respectively, supporting the idea that this receptor plays a role in the microglial response to proinflammatory stimuli. While we did not observe any modulatory effects of selective P2Y14 receptor activation on iNOS or COX-2 pathways in microglia, it remains probable that P2Y14 receptors alter some other microglial inflammatory function(s) not measured here.…”

Section: Discussionmentioning

confidence: 79%

“…Its newly identified presence in microglia [5] suggests that P2Y14 may have a role in modulating microglial responses in the CNS. Uracil-containing sugar nucleotides, such as uridine 5' diphosphoglucose (UDPG) and UDP-galactose (UDP-gal), are selective agonists for the P2Y14 receptor [1], which couples intracellularly to the inhibition of adenylyl cyclase via Gi/o [1,8,10,11] in many cell types. Adenylyl cyclase catalyzes the formation of cyclic AMP, enabling protein kinase A (PKA) to phosphorylate and activate the transcription factor cAMP response element binding protein (CREB), among many others.…”

Section: Introductionmentioning

confidence: 99%

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

Brautigam

Dubyak

Crain

et al. 2008

Purinergic Signalling

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In this study we evaluated the functionality and inflammatory effects of P2Y14 receptors in murine N9 microglia. The selective P2Y14 receptor agonist UDPglucose (UDPG) derived from microbial sources dose dependently stimulated expression of cyclooxygenase-2 and inducible nitric oxide synthase, and potentiated the effects of bacterial lipopolysaccharide on nitric oxide production. However, another selective P2Y14 receptor agonist, UDP-galactose, did not affect these endpoints either alone or in combination with lipopolysaccharide. Interestingly, synthetic UDPG also had no detectable proinflammatory effects, although P2Y14 receptors are both expressed and functional in N9 microglia. While synthetic UDPG decreased levels of phosphorylated cyclic AMP response element binding protein, an effect that was blocked by pertussis toxin, the pro-inflammatory effects of microbial-derived UDPG were insensitive to pertussis toxin. These data suggest that the pro-inflammatory effects of microbial-derived UDPG are independent of P2Y14 receptors and imply that microbial-derived contaminants in the UDPG preparation may be involved in the observed inflammatory effects.

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Section: Discussionmentioning

confidence: 79%

Section: Introductionmentioning

confidence: 99%

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

Brautigam

Dubyak

Crain

et al. 2008

Purinergic Signalling

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“…5). Collectively, these results strongly suggest that UDP-glucose released into CF-like diseased airways acts as a pro-inflammatory mediator, via stimulation of the P2Y 14 R. P2Y 14 R mRNA is expressed in human [45] and murine [46] lungs [17,46] and inflammatory cells [17][18][19][20][21], but the identity of the cell type(s) potentially sensing UDP-glucose in airway surface liquids is not known. We observed no P2Y 14 R mRNA amplification in well-differentiated primary cultures of bronchial epithelial cells (data not shown).…”

Section: Discussionmentioning

confidence: 96%

“…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%

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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“…Unlike other P2 receptors, the human P2Y 14 receptor is activated by UDP-Glc, UDP-GlcNAc, and other UDP-sugars but not by di-or triphosphonucleotides (3). P2Y 14 receptor transcripts are expressed in several human tissues, including placenta, stomach, intestine, adipose, brain, lung, spleen, heart, and circulating leukocytes (3,(5)(6)(7). UDPsugar-promoted signaling has been reported in astrocytes and microglial cells (8,9), lung epithelial cells (10), bone marrow hematopoietic stem cells (11), and multiple types of peripheral immune cells, including neutrophils, lymphocytes, and dendritic cells (6,7,12,13).…”

mentioning

confidence: 99%

Endoplasmic Reticulum/Golgi Nucleotide Sugar Transporters Contribute to the Cellular Release of UDP-sugar Signaling Molecules

Sesma

Esther

Kreda

et al. 2009

Journal of Biological Chemistry

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Extracellular UDP-sugars promote cellular responses by interacting with widely distributed P2Y 14 receptors, but the mechanisms by which these molecules are released from cells are poorly understood. Given the active role of UDP-sugars in glycosylation reactions within the secretory pathway, we hypothesized that UDP-sugar release includes an exocytotic component. This hypothesis was tested by assessing the contribution of endoplasmic reticulum (ER)/Golgi-resident UDPGlcNAc transporters to the cellular release of their cognate substrates. A sensitive and highly selective assay for UDP-GlcNAc mass was developed using purified AGX2, an isoenzyme of human UDP-GlcNAc pyrophosphorylase. Robust constitutive release of UDP-GlcNAc was observed in yeast as well as in well differentiated human airway epithelial cells. The human UDPGlcNAc transporter HFRC1 was overexpressed in human bronchial epithelial cells and was shown to localize in the Golgi and to enhance the surface expression of N-acetylglucosamine-rich glycans. HFRC1-overexpressing cells also displayed increased constitutive and hypotonic stress-stimulated release of UDPGlcNAc. Yeast mutants lacking Yea4 (the ER UDP-GlcNAc transporter endogenously expressed in Saccharomyces cerevisiae) showed reduced UDP-GlcNAc release. Yea4-deficient cells complemented with Yea4 showed UDP-GlcNAc release rates at levels similar to or higher than wild type cells. Our results illustrate that ER/Golgi lumen constitutes a significant source of extracellular UDP-sugars and therefore plays a critical role in nucleotide sugar-promoted cell signaling.Extracellular nucleotides perform important signaling functions via activation of broadly distributed P2X and P2Y purinergic receptors (1, 2). P2X receptors comprise seven species (P2X 1 -P2X 7 ) of ATP-gated ion channels. P2Y receptors belong to the superfamily of G protein-coupled receptors. At least eight human P2Y receptor species have been identified, seven of which (P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 , P2Y 11 , P2Y 12 , and P2Y 13 ) are activated by adenine and/or uridine nucleoside di-and triphos-

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GPR105, a novel Gi/o-coupled UDP-glucose receptor expressed on brain glia and peripheral immune cells, is regulated by immunologic challenge: possible role in neuroimmune function

Cited by 89 publications

References 45 publications

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

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

UDP-glucose promotes neutrophil recruitment in the lung

Endoplasmic Reticulum/Golgi Nucleotide Sugar Transporters Contribute to the Cellular Release of UDP-sugar Signaling Molecules

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