Distribution and functional characterization of equilibrative nucleoside transporter-4, a novel cardiac adenosine transporter activated at acidic pH
Distribution and functional characterization of equilibrative nucleoside transporter-4, a novel cardiac adenosine transporter activated at acidic pH
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DOI：
10.1161/01.res.0000238359.18495.42
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发表时间：
2006-09-01
影响因子：
20.1
通讯作者：
Baldwin, Stephen A.
中科院分区：
文献类型：
--
作者：
Barnes, Kay;Dobrzynski, Halina;Baldwin, Stephen A.
腺苷通过调节冠状动脉血流、心脏起搏和收缩性，在心脏的有效功能中发挥多种作用。先前的研究表明平衡核苷转运蛋白家族成员平衡核苷转运蛋白-1 （ENT1）参与心脏腺苷水平的调节。我们在此报道，该家族的第二个成员ENT4在心脏中也大量存在，特别是在心室肌细胞和血管内皮细胞的质膜中，但与ENT1不同的是，ENT1在窦房结和房室结中几乎不存在。最初被描述为单胺/有机阳离子转运体，我们发现人类和小鼠的ENT4都表现出一种新的，pH依赖的腺苷转运活性，在酸性pH下最佳（在pH 5.5时，K-m值分别为0.78和0.13 mmol/L），在pH 7.4时不存在。相比而言，5 -羟色胺通过ENT4转运对ph相对不敏感。ENT4介导的核苷转运是腺苷选择性的，不依赖于钠，仅被经典的平衡核苷转运抑制剂双嘧达莫、地拉齐普和硝基苄基硫代肌苷微弱抑制。我们假设ENT4除了在心脏5 -羟色胺运输中发挥作用外，还有助于调节细胞外腺苷浓度，特别是在与缺血相关的酸中毒条件下。
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 K-m 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.