Published online before print July 27, 2006, doi: 10.1161/01.RES.0000238359.18495.42
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on February 22, 2006
Revised on July 18, 2006
Accepted on July 19, 2006
Distribution and Functional Characterization of Equilibrative Nucleoside Transporter-4, a Novel Cardiac Adenosine Transporter Activated at Acidic pH
Kay Barnes *;
From the Institute of Membrane and Systems Biology (K.B., S.F., P.R.B., F.I., E.R.S., L.S., R.B.-C., S.A.B.), University of Leeds, UK; Division of Cardiovascular and Endocrine Sciences (H.D., J.T., M.R.B.), University of Manchester, UK; Membrane Protein Research Group (M.W.L.R., C.E.C., J.D.Y.) and Departments of Physiology (M.W.L.R., J.D.Y.) and Oncology (C.E.C.), University of Alberta, and Cross Cancer Institute (C.E.C.), Edmonton, Alberta, Canada; and Department of Biochemistry and Molecular Biology (W.C.C.), Louisiana State, University Health Sciences Center, New Orleans. 8Current address for P.R.B.: Department of Biology, University of York, UK.
* To whom correspondence should be addressed. E-mail: K.Barnes{at}leeds.ac.uk.
Adenosine plays multiple roles in the efficient functioning of the heart by regulating coronary blood flow, cardiac pacemaking, and contractility. Previous studies have implicated the equilibrative nucleoside transporter family member equilibrative nucleoside transporter-1 (ENT1) in the regulation of cardiac adenosine levels. We report here that a second member of this family, ENT4, is also abundant in the heart, in particular in the plasma membranes of ventricular myocytes and vascular endothelial cells but, unlike ENT1, is virtually absent from the sinoatrial and atrioventricular nodes. Originally described as a monoamine/organic cation transporter, we found that both human and mouse ENT4 exhibited a novel, pH-dependent adenosine transport activity optimal at acidic pH (apparent Km values 0.78 and 0.13 mmol/L, respectively, at pH 5.5) and absent at pH 7.4. In contrast, serotonin transport by ENT4 was relatively insensitive to pH. ENT4-mediated nucleoside transport was adenosine selective, sodium independent and only weakly inhibited by the classical inhibitors of equilibrative nucleoside transport, dipyridamole, dilazep, and nitrobenzylthioinosine. We hypothesize that ENT4, in addition to playing roles in cardiac serotonin transport, contributes to the regulation of extracellular adenosine concentrations, in particular under the acidotic conditions associated with ischemia.
Key words: nucleoside • adenosine • transport • ischemia • pH
This article has been cited by other articles:
 |
|
 |
|
  K. M. Hoque, L. Chen, G. P. H. Leung, and C.-M. Tse A purine-selective nucleobase/nucleoside transporter in PK15NTD cells Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2008; 294(6): R1988 - R1995. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Markovic, M. Segal, B. Djuricic, and Z. Redzic Kinetics of nucleoside uptake by the basolateral side of the sheep choroid plexus epithelium perfused in situ Exp Physiol, March 1, 2008; 93(3): 325 - 333. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. B. Rose and I. R. Coe Physiology of Nucleoside Transporters: Back to the Future. . . . Physiology, February 1, 2008; 23(1): 41 - 48. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Govindarajan, A. H. Bakken, K. L. Hudkins, Y. Lai, F. J. Casado, M. Pastor-Anglada, C.-M. Tse, J. Hayashi, and J. D. Unadkat In situ hybridization and immunolocalization of concentrative and equilibrative nucleoside transporters in the human intestine, liver, kidneys, and placenta Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2007; 293(5): R1809 - R1822. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Zhou, L. Xia, and J. Wang Metformin Transport by a Newly Cloned Proton-Stimulated Organic Cation Transporter (Plasma Membrane Monoamine Transporter) Expressed in Human Intestine Drug Metab. Dispos., October 1, 2007; 35(10): 1956 - 1962. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. L. Damaraju, A. N. Elwi, C. Hunter, P. Carpenter, C. Santos, G. M. Barron, X. Sun, S. A. Baldwin, J. D. Young, J. R. Mackey, et al. Localization of broadly selective equilibrative and concentrative nucleoside transporters, hENT1 and hCNT3, in human kidney Am J Physiol Renal Physiol, July 1, 2007; 293(1): F200 - F211. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Visser, L. Sun, V. Damaraju, T. Tackaberry, Y. Peng, M. J. Robins, S. A. Baldwin, J. D. Young, and C. E. Cass Residues 334 and 338 in Transmembrane Segment 8 of Human Equilibrative Nucleoside Transporter 1 Are Important Determinants of Inhibitor Sensitivity, Protein Folding, and Catalytic Turnover J. Biol. Chem., May 11, 2007; 282(19): 14148 - 14157. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Loffler, J. C. Morote-Garcia, S. A. Eltzschig, I. R. Coe, and H. K. Eltzschig Physiological Roles of Vascular Nucleoside Transporters Arterioscler. Thromb. Vasc. Biol., May 1, 2007; 27(5): 1004 - 1013. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Zhou, L. Xia, K. Engel, and J. Wang Molecular Determinants of Substrate Selectivity of a Novel Organic Cation Transporter (PMAT) in the SLC29 Family J. Biol. Chem., February 2, 2007; 282(5): 3188 - 3195. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. K. Bubien and D. J. Benos Molecular pH Probes: Mediators of Angina and Ischemic Preconditioning? Circ. Res., September 1, 2006; 99(5): 453 - 454. [Full Text] [PDF]
|
|