期刊
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
卷 302, 期 4, 页码 G447-G459出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpgi.00165.2011
关键词
P1 receptors; P2 receptors; ATP; fibrosis; carbon tetrachloride intoxication; nucleoside triphosphate diphosphohydrolases
资金
- Canadian Institutes of Health Research (CIHR) [MOP-102472]
- National Institutes of Health (NIH/NIDDK) [R01 DK076735, R01 DK070849]
- Yale Liver Center [DK 45710]
- Government of Gabon
- American Liver Foundation
- Egyptian Government Ministry of Higher Education
- Institut National de la Sante et de la Recherche Medicale
- Fonds de Recherche en Sante du Quebec (FRSQ)
- Heart and Stroke Foundation of Canada
- Canadian Stroke Network
Fausther M, Lecka J, Soliman E, Kauffenstein G, Pelletier J, Sheung N, Dranoff JA, Sevigny J. Coexpression of ecto-5'-nucleotidase/CD73 with specific NTPDases differentially regulates adenosine formation in the rat liver. Am J Physiol Gastrointest Liver Physiol 302: G447-G459, 2012. First published December 1, 2011; doi:10.1152/ajpgi.00165.2011.-Ectonucleotidases modulate purinergic signaling by hydrolyzing ATP to adenosine. Here we characterized the impact of the cellular distribution of hepatic ectonucleotidases, namely nucleoside triphosphate diphosphohydrolase (NTPDase)1/CD39, NTPDase2/CD39L1, NTPDase8, and ecto-5'-nucleotidase/CD73, and of their specific biochemical properties, on the levels of P1 and P2 receptor agonists, with an emphasis on adenosine-producing CD73. Immunostaining and enzyme histochemistry showed that the distribution of CD73 (protein and AMPase activity) overlaps partially with those of NTPDase1, -2, and -8 (protein levels and ATPase and ADPase activities) in normal rat liver. CD73 is expressed in fibroblastic cells located underneath vascular endothelial cells and smooth muscle cells, which both express NTPDase1, in portal spaces in a distinct fibroblast population next to NTPDase2-positive portal fibroblasts, and in bile canaliculi, together with NTPDase8. In fibrotic rat livers, CD73 protein expression and activity are redistributed but still overlap with the NTPDases mentioned. The ability of the observed combinations of ectonucleotidases to generate adenosine over time was evaluated by reverse-phase HPLC with the recombinant rat enzymes at high inflammatory (500 mu M) and low physiological (1 mu M) ATP concentrations. Overall, ATP was rapidly converted to adenosine by the NTPDase1 + CD73 combination, but not by the NTPDase2 + CD73 combination. In the presence of NTPDase8 and CD73, ATP was sequentially dephosphorylated to the CD73 inhibitor ADP, and then to AMP, thus resulting in a delayed formation of adenosine. In conclusion, the specific cellular cocompartmentalization of CD73 with hepatic NTPDases is not redundant and may lead to the differential activation of P1 and P2 receptors, under normal and fibrotic conditions.
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