Human organic anion transporter 2 is distinct from organic anion transporters 1 and 3 with respect to transport function
Human organic anion transporter 2 is distinct from organic anion transporters 1 and 3 with respect to transport function
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DOI：
10.1152/ajprenal.00140.2015
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发表时间：
2015-11-15
影响因子：
4.2
通讯作者：
Burckhardt, Birgitta C.
中科院分区：
文献类型：
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作者：
Henjakovic, Maja;Hagos, Yohannes;Burckhardt, Birgitta C.
从系统发育上来说，有机阴离子转运蛋白 (OAT)1 和 OAT3 关系密切，而 OAT2 关系较远。使用稳定转染人 OAT1、OAT2 或 OAT3 的人胚胎肾 293 细胞进行实验，以比较选定的转运特性。 OAT1、OAT2 和 OAT3 的共同点是它们都具有转运 cGMP 的能力。 OAT2与前列腺素相互作用，并且cGMP摄取被PGE(2)和PGF(2α)抑制，IC50值分别为40.8和12.7μM。 OAT1（IC50：23.7μM）、OAT2（IC50：9.5μM）和OAT3（IC50：1.6μM）被MK571（一种已确定的多药耐药蛋白抑制剂）有效抑制。 OAT2 介导的 cGMP 摄取不受短链单羧酸盐抑制，并且与 OAT1 和 OAT3 不同，不受二羧酸盐抑制。因此，OAT2 没有表现出 cGMP/戊二酸交换。 OAT1 和 OAT3 表现出 pH 和 Cl- 依赖性，分别在酸性 pH 下具有较高的底物吸收，而在没有 Cl- 的情况下则具有较低的底物吸收。 OAT2 没有观察到这种 pH 和 Cl 依赖性。在 K-1 离子载体缬氨霉素存在下，高 K-1 浓度使膜电位去极化，但 cGMP 摄取不受影响。除了 cGMP 之外，OAT2 还转运尿酸盐和谷氨酸，但无法证明 cGMP/谷氨酸交换。这些实验表明，OAT2 介导的 cGMP 摄取不是通过与单羧酸盐、二羧酸盐和羟基离子的交换发生的。电中性 cGMP 摄取的抗衡阴离子仍有待确定。
Phylogentically, organic anion transporter (OAT)1 and OAT3 are closely related, whereas OAT2 is more distant. Experiments with human embryonic kidney-293 cells stably transfected with human OAT1, OAT2, or OAT3 were performed to compare selected transport properties. Common to OAT1, OAT2, and OAT3 is their ability to transport cGMP. OAT2 interacted with prostaglandins, and cGMP uptake was inhibited by PGE(2) and PGF(2 alpha) with IC50 values of 40.8 and 12.7 mu M, respectively. OAT1 (IC50: 23.7 mu M), OAT2 (IC50: 9.5 mu M), and OAT3 (IC50: 1.6 mu M) were potently inhibited by MK571, an established multidrug resistance protein inhibitor. OAT2-mediated cGMP uptake was not inhibited by short-chain monocarboxylates and, as opposed to OAT1 and OAT3, not by dicarboxylates. Consequently, OAT2 showed no cGMP/glutarate exchange. OAT1 and OAT3 exhibited a pH and a Cl- dependence with higher substrate uptake at acidic pH and lower substrate uptake in the absence of Cl-, respectively. Such pH and Cl- dependencies were not observed with OAT2. Depolarization of membrane potential by high K-1 concentrations in the presence of the K-1 ionophore valinomycin left cGMP uptake unaffected. In addition to cGMP, OAT2 transported urate and glutamate, but cGMP/glutamate exchange could not be demonstrated. These experiments suggest that OAT2-mediated cGMP uptake does not occur via exchange with monocarboxylates, dicarboxylates, and hydroxyl ions. The counter anion for electroneutral cGMP uptake remains to be identified.