Adenosine Deaminase 1 and Concentrative Nucleoside Transporters 2 and 3 Regulate Adenosine on the Apical Surface of Human Airway Epithelia:  Implications for Inflammatory Lung Diseases

Hirsh, Andrew J.; Stonebraker, Jaclyn R.; Heusden, Catja A. Van; Lazarowski, Eduardo R.; Boucher, Richard C.; Picher, Maryse

doi:10.1021/bi7009647

Cited by 41 publications

(39 citation statements)

References 65 publications

(130 reference statements)

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“…The mRNA expression levels in noninflamed tissues were set to 1. ‫,ء‬ P Ͻ 0.05; ‫,ءء‬ P Ͻ 0.01; ‫,ءءء‬ P Ͻ 0.0001. adenosine, and may be responsible for inflammation of the tissue, similarly to the mechanism proposed for inflammatory lung diseases (Hirsh et al, 2007). In support of this finding, mRNA levels of nucleoside transporters are elevated in the inflamed tissues of IBD patients ( Figs.…”

Section: Discussionsupporting

confidence: 71%

Changes in mRNA Expression Levels of Solute Carrier Transporters in Inflammatory Bowel Disease Patients

Wojtal¹,

Eloranta²,

Hrúz³

et al. 2009

Drug Metab Dispos

135

111

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ABSTRACT:Inflammatory bowel disease (IBD) is an inflammatory condition that affects the gastrointestinal tract. The solute carrier (SLC) superfamily of transporters comprise proteins involved in the uptake of drugs, hormones, and other biologically active compounds. The purpose of this study was to determine the mRNA expression levels of 15 solute carrier transporters in two regions of the intestine in IBD patients. Endoscopic biopsy specimens were taken from two locations (terminal ileum and colon) for histological examination and RNA extraction. We quantitatively measured the mRNA expression of 15 SLC transporters in 107 IBD patients (53 with Crohn's disease and 54 with ulcerative colitis) and 23 control subjects. mRNA expression was evaluated using the quantitative reverse transcription-polymerase chain reaction technique. We observed that in the ileum of IBD patients, mRNA levels for serotonin transporter, equilibrative nucleoside transporter (ENT) 1, ENT2, and organic anion-transporting polypeptide (OATP) 2B1 were significantly elevated, whereas levels for apical sodium-dependent bile acid transporter (ASBT) and organic zwitterion/cation transporter (OCTN) 2 were significantly lower. In colon, mRNA levels for ENT1, ENT2, concentrative nucleoside transporter (CNT) 2, OATP2B1, and OATP4A1 were significantly higher, whereas mRNA levels for OCTN2 were significantly decreased. In inflamed colon of IBD patients the mRNA expression levels of ENT1, ENT2, CNT2, OATP2B1, OATP4A1, and peptide transporter 1 were significantly higher. We conclude that intestinal SLC mRNA levels are dysregulated in IBD patients, which may be linked to the inflammation of the tissue and provides an indication about the role of inflammatory signaling in regulation of SLC expression.

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Section: Discussionsupporting

confidence: 71%

Changes in mRNA Expression Levels of Solute Carrier Transporters in Inflammatory Bowel Disease Patients

Wojtal¹,

Eloranta²,

Hrúz³

et al. 2009

Drug Metab Dispos

135

111

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“…Furthermore, luminal ADO is absorbed via the enterocyte nucleoside transporters (NTs), such as concentrative NT (CNT or SLC28) and the equilibrative NT (ENT or SLC29) (Pastor-Anglada et al, 2007). These observations suggest that luminal ADO signaling activity may be affected by ADA and NT activity, as reported in the airway epithelium (Hirsh et al, 2007). Furthermore, apical CNT activity is thought to mediate ADO uptake into the epithelial cells, where it can be recycled to ATP, metabolized, or released across the basolateral membrane (Ritzel et al, 1998).…”

Section: Introductionmentioning

confidence: 94%

Endogenous Luminal Surface Adenosine Signaling Regulates Duodenal Bicarbonate Secretion in Rats

Ham

Mizumori²,

Watanabe³

et al. 2010

J Pharmacol Exp Ther

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Luminal ATP increases duodenal bicarbonate secretion (DBS) via brush border P2Y receptors. Because ATP is sequentially dephosphorylated to adenosine (ADO) and the brush border highly expresses adenosine deaminase (ADA), we hypothesized that luminal [ADO] regulators and sensors, including P1 receptors, ADA, and nucleoside transporters (NTs) regulate DBS. We measured DBS with pH and CO 2 electrodes, perfusing ADO Ϯ adenosine receptor agonists or antagonists or the cystic fibrosis transmembrane conductance regulator (CFTR) inhibitor CFTR inh -172 on DBS. Furthermore, we examined the effect of inhibitors of ADA or NT on DBS. Perfusion of AMP or ADO (0.1 mM) uniformly increased DBS, whereas inosine had no effect. The A 1/2 receptor agonist 5Ј-(N-ethylcarboxamido)-adenosine (0.1 mM) increased DBS, whereas ADO-augmented DBS was inhibited by the potent A 2B receptor antagonist N-(4-cyanophenyl)-2-[4-(2,3,6,7-tetrahydro-2,6-dioxo-1,3-dipropyl-1H-purin-8-yl)phenoxy]-acetamide (MRS1754) (10 M). Other selective adenosine receptor agonists or antagonists had no effect. The A 2B receptor was immunolocalized to the brush border membrane of duodenal villi, whereas the A 2A receptor was immunolocalized primarily to the vascular endothelium. Furthermore, ADO-induced DBS was enhanced by 2Ј-deoxycoformycin (1 M) and formycin B (0.1 mM), but not by S-(4-nitrobenzyl)-6-thioinosine (0.1 mM), and it was abolished by CFTR inh -172 pretreatment (1 mg/kg i.p). Moreover, ATP (0.1 mM)-induced DBS was partially reduced by (1R,2S,4S,5S)-4-2-iodo-6-(methylamino)-9H-purin-9-yl]-2-(phosphonooxy)bicyclo[3.1.0] hexane-1-methanol dihydrogen phosphate ester tetraammonium salt (MRS2500) or 8-[4-[4-(4-chlorophenzyl)piperazide-1-sulfonyl) phenyl]]-1-propylxanthine (PSB603) and abolished by both, suggesting that ATP is sequentially degraded to ADO. Luminal ADO stimulates DBS via A 2B receptors and CFTR. ATP release, ectophosphohydrolases, ADA, and concentrative NT may coordinately regulate luminal surface ADO concentration to modulate ADO-P1 receptor signaling in rat duodenum.

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“…1A). We used the drugs at concentrations that were previously employed (14,23,42). None of these drugs affected the production of adenosine in unstretched tissue or during experimental filling.…”

Section: Distinct Pathways For Adenosine Biogenesis Are Found At the mentioning

confidence: 99%

Modulation of bladder function by luminal adenosine turnover and A₁receptor activation

Prakasam

Herrington

Roppolo

et al. 2012

American Journal of Physiology-Renal Physiology

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The bladder uroepithelium transmits information to the underlying nervous and musculature systems, is under constant cyclical strain, expresses all four adenosine receptors (A 1, A2A, A2B, and A3), and is a site of adenosine production. Although adenosine has a welldescribed protective effect in several organs, there is a lack of information about adenosine turnover in the uroepithelium or whether altering luminal adenosine concentrations impacts bladder function or overactivity. We observed that the concentration of extracellular adenosine at the mucosal surface of the uroepithelium was regulated by ecto-adenosine deaminase and by equilibrative nucleoside transporters, whereas adenosine kinase and equilibrative nucleoside transporters modulated serosal levels. We further observed that enriching endogenous adenosine by blocking its routes of metabolism or direct activation of mucosal A 1 receptors with 2-chloro-N 6 -cyclopentyladenosine (CCPA), a selective agonist, stimulated bladder activity by lowering the threshold pressure for voiding. Finally, CCPA did not quell bladder hyperactivity in animals with acute cyclophosphamideinduced cystitis but instead exacerbated their irritated bladder phenotype. In conclusion, we find that adenosine levels at both surfaces of the uroepithelium are modulated by turnover, that blocking these pathways or stimulating A1 receptors directly at the luminal surface promotes bladder contractions, and that adenosine further stimulates voiding in animals with cyclophosphamide-induced cystitis.cyclophosphamide-induced cystitis; voiding ADENOSINE IS A UBIQUITOUSLY occurring nucleoside that is important for the homeostasis of diverse organ systems including the kidneys, heart, lungs, and brain (20,46,55). It is found both intracellularly and in the extracellular space, and its concentration in these compartments is dependent on its biogenesis and turnover (43,44). The intracellular pool of adenosine is synthesized de novo by the hydrolysis of S-adenosylmethionine or is generated from the nucleotidase-dependent breakdown of ATP to ADP to AMP to adenosine. The extracellular pool of adenosine is also formed from the hydrolysis of ATP by ecto-nucleotidases or alkaline phosphatases or by metabolism of cAMPs to AMPs to adenosine. In addition, sodiumcoupled concentrative or equilibrative nucleoside transporters shuttle adenosine in a concentration-dependent manner between the intracellular and extracellular compartments (23). The turnover of extracellular and intracellular adenosine is mediated by two enzymes: adenosine deaminase and adenosine kinase, which decrease adenosine by converting it to inosine or AMP, respectively (13,30,32,52).

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Adenosine Deaminase 1 and Concentrative Nucleoside Transporters 2 and 3 Regulate Adenosine on the Apical Surface of Human Airway Epithelia: Implications for Inflammatory Lung Diseases

Cited by 41 publications

References 65 publications

Changes in mRNA Expression Levels of Solute Carrier Transporters in Inflammatory Bowel Disease Patients

Changes in mRNA Expression Levels of Solute Carrier Transporters in Inflammatory Bowel Disease Patients

Endogenous Luminal Surface Adenosine Signaling Regulates Duodenal Bicarbonate Secretion in Rats

Modulation of bladder function by luminal adenosine turnover and A₁receptor activation

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Adenosine Deaminase 1 and Concentrative Nucleoside Transporters 2 and 3 Regulate Adenosine on the Apical Surface of Human Airway Epithelia: Implications for Inflammatory Lung Diseases

Cited by 41 publications

References 65 publications

Changes in mRNA Expression Levels of Solute Carrier Transporters in Inflammatory Bowel Disease Patients

Changes in mRNA Expression Levels of Solute Carrier Transporters in Inflammatory Bowel Disease Patients

Endogenous Luminal Surface Adenosine Signaling Regulates Duodenal Bicarbonate Secretion in Rats

Modulation of bladder function by luminal adenosine turnover and A1receptor activation

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Product

Resources

About

Modulation of bladder function by luminal adenosine turnover and A₁receptor activation