Abstract
Concentrative and Equilibrative Nucleoside Transporter proteins (CNT and ENT, respectively) are encoded by gene families SLC28 and SLC29. They mediate the uptake of natural nucleosides and a variety of nucleoside-derived drugs, mostly used in anticancer therapy. CNT and ENT proteins are mostly localized in the apical and basolateral sides, respectively, in (re)absorptive epithelia. This anatomic distribution determines nucleoside and nucleoside-derived vectorial flux. CNT expression (particularly CNT2) is associated with differentiation and is also nutritionally regulated in intestinal epithelia, whereas ENT protein amounts (mostly ENT1) are increased when cells are exposed to proliferative stimuli such as EGF, TGF-α or wounding. Although all these features suggest a role for NT proteins in nucleoside salvage and (re)absorption, recent data demonstrate that CNT2 might be under purinergic control, in a manner that is dependent on energy metabolism. A physiological link between CNT2 function and intracellular metabolism is also supported by the evidence that extracellular adenosine can activate the AMP-dependent kinase (AMPK), by a mechanism which relies upon adenosine transport and phosphorylation. Thus the complex pattern of NT isoform expression in mammalian cells can fulfill physiological roles other than salvage.
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Aymerich, I., Duflot, S., Fernández-Veledo, S., Guillén-Gómez, E., Huber-Ruano, I., Casado, F. J. and Pastor-Anglada, M. (2005):Biochem. Soc. Trans.,33(Pt 1), 216–219.
Aymerich, I., Foufelle, F., Ferre, P., Casado, F. J. and Pastor-Anglada, M. (2005):J. Cell Sci.,119 (Pt 8), 1612–1621.
Aymerich, I., Pastor-Anglada, M. and Casado, F. J. (2004):J. Gen. Physiol.,124(5), 505–512.
Badagnani, I., Chan, W., Castro, R. A., Brett, C. M., Huang, C. C., Stryke, D., Kawamoto, M., Johns, S. J., Ferrin, T. E., Carlson, E. J., Burchard, E. G. and Giacomini, K. M. (2005):Pharmacogenomics J.,5(3), 157–165.
Bronk, J. R. and Hastewell, J. G. (1989):J. Physiol.,408, 405–411.
Casanello, P., Torres, A., Sanhueza, F., González, M., Farias, M., Gallardo, V., Pastor-Anglada, M., San Martín, R. and Sobrevia, L. (2005):Circ. Res.,97(1), 16–24.
Choi, D. S., Cascini, M. G., Mailliard, W., Young, H., Paredes, P., McMahon, T., Diamond, I., Bonci, A. and Messing, R. O. (2004):Nat. Neurosci.,7(8), 855–861.
Chow, L., Lai, R., Dabbagh, L., Belch, A., Young, J. D., Cass, C. E. and Mackey, J. R. (2005):Mod. Pathol.,18(4), 558–564.
Daniel, H. (2004):Annu. Rev. Physiol.,66 361–384.
Del Santo, B., Valdés, R., Mata, J., Felipe, A., Casado, F. J. and Pastor-Anglada, M. (1998):Hepatology,28(6), 1504–1511.
Dixon, A. K., Gubitz, A. K., Sirinathsinghji, D. J., Richardson, P. J. and Freeman, T. C. (1996):Br. J. Pharmacol.,118, 1461–1468.
Doherty, A. J. and Jarvis, S. M. (1993):Biochim. Biophys. Acta,1147(2), 214–222.
Duflot, S., Calvo, M., Casado, F. J., Enrich, C. and Pastor-Anglada, M. (2002):Exp. Cell Res,281(1), 77–85.
Duflot, S., Riera, B., Fernández-Veledo, S., Casado, V., Norman, R. I., Casado, F. J., Lluis, C., Franco, R. and Pastor-Anglada, M. (2004):Mol. Cell. Biol.,24(7), 2710–2719.
Farre, X., Guillén-Gómez, E., Sánchez, L., Hardisson, D., Plaza, Y., Lloberas, J., Casado, F. J. and Pastor-Anglada, M. (2004):Int. J. Cancer,112(6), 959–966.
Fernández-Veledo, S., Jover, R., Casado, F. J., Gómez-Lechon, M. J. and Pastor-Anglada, M. (2007):Biochem. Biophys. Res. Commun.,353(2), 381–388.
Fernández-Veledo, S., Huber-Ruano, I., Aymerich, I., Duflot, S., Casado, F. J. and Pastor-Anglada, M. (2006):Biochem. J.,395(2), 337–344.
Fernández-Veledo, S., Valdés, R., Wallenius, V., Casado, F. J. and Pastor-Anglada, M. (2004):J. Hepatol.,41(4), 538–544.
Ferraris, R. P. (2001):Biochem. J.,360(Pt 2), 265–276.
Goh, L. B., Mack, P. and Lee, C. W. (1995):Anticancer Res.,15, 2575–2580.
Gray, J. H., Mangravite, L. M., Owen, R. P., Urban, T. J., Chan, W., Carlson, E. J., Huang, C. C., Kawamoto, M., Johns, S. J., Stryke, D., Ferrin, T. E. and Giacomini, K. M. (2004):Mol. Pharmacol.,65(3), 512–519.
Gray, J. H., Owen, R. P. and Giacomini, K. M. (2004):Pflugers Arch.,447(5), 728–734.
Griffiths, M., Yao, S. Y., Abidi, F., Phillips, S. E., Cass, C. E., Young, J. D. and Baldwin, S. A. (1997):Biochem. J.,328(Pt 3), 739–743.
Guillén-Gómez, E., Calbet, M., Casado, J., de Lecea, L., Soriano, E., Pastor-Anglada, M. and Burgaya, F. (2004):J. Neurochem.,90(4), 883–893.
Gutiérrez, M. M. and Giacomini, K. M. (1993):Biochim. Biophys. Acta,1149(2), 202–208.
Hamilton, S. R., Yao, S. Y., Ingram, J. C., Hadden, D. A., Ritzel, M. W., Gallagher, M. P., Henderson, P. J., Cass, C. E., Young, J. D. and Baldwin, S. A. (2001):J. Biol. Chem.,276(30), 27981–27988.
Hansen, P. B. and Schnermann, J. (2003):Am. J. Physiol. Renal Physiol.,285, 590–599.
Huang, Q. Q., Yao, S. Y., Ritzel, M. W., Paterson, A. R., Cass, C. E. and Young, J. D. (1994):J. Biol. Chem.,269(27), 17757–17760.
Hyde, R., Taylor, P. M. and Hundal, H. S. (2003):Biochem. J.,373(Pt 1), 1–18.
Iwasa, Y., Iwasa, M., Ohmori, Y., Fukutomi, T. and Ogoshi, S. (2000):Nutrition,16(7–8), 598–602.
Jakobs, E. S., Van Os-Corby D. J. and Paterson, A. R. (1990):J. Biol. Chem.,265(36), 22210–22216.
Janas, L. M. and Picciano, M. F. (1982):Pediatr. Res,16(8), 659–662.
Kimura, Y., Turner, J. R., Braasch, D. A. and Buddington, R. K. (2005):Am. J. Physiol. Gastrointest. Liver Physiol.,289(6), 1007–1014.
King, A. E., Ackley, M. A., Cass, C. E., Young, J. D. and Baldwin, S. A. (2006):Trends Pharmacol. Sci.,27(8), 416–25.
Kong, W., Engel, K. and Wang, J. (2004):Curr. Drug Metab.,5(1), 63–84.
Kuttesch, J. F. and Nelson, J. A. (1982):Cancer Chemother. Pharmacol.,8(2), 221–229.
Lai, Y., Bakken, A. H. and Unadkat, J. D. (2002):J. Biol. Chem.,277(40), 37711–37717.
Lang T. T., Selner M., Young, J.D. and Cass, C. E. (2001):Mol. Pharmacol.,60, 1143–1152.
Larráyoz, I. M., Casado, F. J., Pastor-Anglada, M. and Lostao, M. P. (2004):J. Biol. Chem.,279(10), 8999–9007.
Lee, W., Kanai, Y., Wells, R. G. and Hediger, M. A. (1994):J. Biol. Chem.,269, 12032–12039.
López-Navarro, A. T., Ortega, M. A., Peragon, J., Bueno, J. D., Gil, A. and Sánchez-Pozo, A. (1996):Gastroenterology,110(6), 1760–1769.
Lu, H., Chen, C. and Klaassen, C. (2004):Drug Metab. Dispos.,32(12), 1455–1461.
Mackey, J. R., Yao, S. Y., Smith, K. M., Karpinski, E., Baldwin, S. A., Cass, C. E. and Young, J. D. (1999):J. Natl. Cancer Inst.,91, 1876–1881.
Mangravite, L. M., Badagnani, I. and Giacomini, K. M. (2003):Eur. J. Pharmacol.,479, 269–281.
Mangravite, L. M., Xiao, G. and Giacomini, K. M. (2003):Am. J. Physiol. Renal Physiol.,284(5), 902–910.
Ngo, L. Y., Patil, S. D. and Unadkat, J. D. (2001):Am. J. Physiol. Gastrointest. Liver Physiol.,280(3), 475–481.
Owen, R. P., Gray, J. H., Taylor, T. R., Carlson, E. J., Huang, C. C., Kawamoto, M., Johns, S. J., Stryke, D., Ferrin, T. E. and Giacomini, K. M. (2005):Pharmacogenet. Genomics,15(2), 83–90.
Pastor-Anglada, M. and Baldwin, S. A. (2001):Drug Develop. Res.,52, 431–43.
Pastor-Anglada, M., Cano-Soldado, P., Molina-Arcas, M., Lostao, M. P., Larráyoz, I., Martínez-Picado, J. and Casado, F. J. (2005):Virus Res.,107(2), 151–164.
Pastor-Anglada, M., Felipe, A., Casado, F. J., del Santo, B., Mata, J. F. and Valdés, R. (1998):Biochem. Cell Biol.,76(5), 771–777.
Patil, S. D. and Unadkat, J. D. (1997):Am. J. Physiol.,272(6 Pt 1), 1314–1320.
Pinto-Duarte, A., Coelho, J. E., Cunha, R. A., Ribeiro, J. A. and Sebastiao, A. M. (2005): J. Neurochem.,93(3), 595–604.
Pressacco, J., Mitrovsky, B., Erlichman, C. and Hedley, D. W. (1995):Cancer Res.,55(7), 1505–1518.
Pressacco, J., Wiley, J. S., Jamieson, G. P., Erlichman, C. and Hedley, D. W. (1995):Br. J. Cancer,72(4), 939–942.
Ritzel, M. W., Ng, A. M., Yao, S. Y., Graham, K., Loewen, S. K., Smith, K. M., Ritzel, R. G., Mowles, D. A., Carpenter, P., Chen, X. Z., Karpinski, E., Hyde, R. J., Baldwin, S. A., Cass, C. E. and Young, J. D. (2001):J. Biol. Chem.,276(4), 2914–2927.
Ritzel, M. W., Yao, S. Y., Ng, A. M., Mackey, J. R., Cass, C. E. and Young, J. D. (1998):Mol.Membr. Biol.,15(4), 203–211.
Rodríguez-Mulero, S., Errasti-Murugarren, E., Ballarin, J., Felipe, A., Doucet, A., Casado, F. J. and Pastor-Anglada, M. (2005):Kidney Int.,68(2), 665–72.
San Martín, R. and Sobrevia, L. (2006):Placenta,27(1), 1–10.
Sato, N., Murakami, Y., Nakano, T., Sugawara, M., Kawakami, H., Idota, T. and Nakajima, I. (1995):Biosci. Biotechnol. Biochem.,59(7), 1267–1271.
Silbernagl, S. (1998):Physiol. Rev.,68, 911–1007.
Smith, K. M., Ng, A. M., Yao, S. Y., Labedz, K. A., Knaus, E. E., Wiebe, L. I., Cass, C. E., Baldwin, S. A., Chen, X. Z., Karpinski, E. and Young J. D. (2004):J. Physiol.,558(Pt 3), 807–823.
Smith, K. M., Slugoski, M. D., Loewen, S. K., Ng, A. M., Yao, S. Y., Chen, X. Z., Karpinski, E., Cass, C. E., Baldwin, S. A. and Young, J. D. (2005):J. Biol. Chem.,280(27), 25436–25449.
Soler, C., García-Manteiga, J., Valdes, R., Xaus, J., Comalada, M., Casado, F. J., Pastor-Anglada, M., Celada, A. and Felipe, A. (2001):FASEB J.,15(11), 1979–1988.
Soler, C., García-Manteiga, J., Valdés, R., Xaus, J., Comalada, M., Casado, F. J., Modolell, M., Nicholson, B., MacLeod, C., Felipe, A., Celada, A. and Pastor-Anglada, M. (2001):J. Biol. Chem.,276(32), 30043–30049.
Spratlin, J., Sangha, R., Glubrecht, D., Dabbagh, L., Young, J. D., Dumontet, C., Cass, C., Lai, R. and Mackey, J. R. (2004):Clin. Cancer Res,10(20), 6956–6961.
Stow, R. A. and Bronk, J. R. (1993):J. Physiol.,468, 311–324.
Sundaram, M., Yao, S. Y., Ingram, J. C., Berry, Z. A., Abidi, F., Cass, C. E., Baldwin, S. A. and Young, J. D. (2001):J. Biol. Chem.,276(48), 45270–45275.
Sundaram, M., Yao, S. Y., Ng, A. M., Cass, C. E., Baldwin, S. A. and Young, J. D. (2001):Biochemistry,40(27), 8146–8151.
Sundaram, M., Yao, S. Y., Ng, A. M., Griffiths, M., Cass, C. E., Baldwin, S. A. and Young, J. D. (1998):J. Biol. Chem.,273(34), 21519–21525.
Thomson, S., Bao, D., Deng, A. and Vallon, V. (2000):J. Clin. Invest.,106, 289–298.
Trimble, M. E. and Coulson, R. (1984):Am. J. Physiol.,246(6 Pt 2), 794–803.
Valdés, R., Fernández-Veledo, S., Aymerich, I., Casado, F. J. and Pastor-Anglada, M. (2006):Cell. Mol. Life Sci.,63(21), 2527–2537.
Valdés, R., Ortega, M. A., Casado, F. J., Felipe, A., Gil, A., Sánchez-Pozo, A. and Pastor-Anglada, M. (2000):Gastroenterology,119(6), 1623–1630.
Van Aubel, R. A., Masereeuw, R. and Russel, F. G. (2000):Am. J. Physiol. Renal Physiol.,279, 216–232.
Vickers, M. F., Mani, R. S., Sundaram, M., Hogue, D. L., Young, J. D., Baldwin, S. A. and Cass, C. E. (1999):Biochem. J.,339 (Pt 1), 21–32.
Visser, F., Vickers, M. F., Ng, A. M., Baldwin, S. A., Young, J. D. and Cass, C. E. (2002):J. Biol. Chem.,277(1), 395–401.
Wang, J., Giacomini, K. M. (1997):J. Biol. Chem.,272(46), 28845–288488.
Wang, J., Su, S. F. and Dresser, M. J. (1997):Am. J. Physiol.,273, 1058–1065.
Ward J. L. and Tse, C. M. (1999):Biochim. Biophys. Acta,1419(1), 15–22.
Ward, J. L., Leung, G. P., Toan, S. V. and Tse, C. M. (2003):Arch. Biochem. Biophys.,411(1), 19–26.
Yao, S. Y., Ng, A. M., Sundaram, M., Cass, C. E., Baldwin, S. A. and Young, J. D. (2001):Mol. Membr. Biol.,18(2), 161–167.
Yao, S. Y., Ng, A. M., Vickers, M. F., Sundaram, M., Cass, C. E., Baldwin, S. A. and Young, J. D. (2002):J. Biol. Chem.,277(28), 24938–24948.
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Pastor-Anglada, M., Errasti-Murugarren, E., Aymerich, I. et al. Concentrative nucleoside transporters (CNTs) in epithelia: from absorption to cell signaling. J Physiol Biochem 63, 97–110 (2007). https://doi.org/10.1007/BF03174089
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DOI: https://doi.org/10.1007/BF03174089