Published online before print July 27, 2006, doi: 10.1161/01.RES.0000238359.18495.42
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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
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