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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Transport direction determines the kinetics of substrate transport by the glutamate transporter EAAC1
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Transport direction determines the kinetics of substrate transport by the glutamate transporter EAAC1

机译：转运方向决定了谷氨酸转运蛋白EAAC1转运底物的动力学

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摘要

Glutamate transport by the excitatory amino acid carrier EAAC1 is known to be reversible. Thus, glutamate can either be taken up into cells, or it can be released from cells through reverse transport, depending on the electrochemical gradient of the co- and coun tertransported ions. However, it is unknown how fast and by which reverse transport mechanism glutamate can be released from cells. Here, we determined the steady- and pre-steady-state kinetics of reverse glutamate transport with submillisecond time resolution. First, our results suggest that glutamate and Na~+ dissociate from their cytoplasmic binding sites sequentially, with glutamate dissociating first, followed by the three cotransported Na~+ ions. Second, the kinetics of glutamate transport depend strongly on transport direction, with reverse transport being faster but less voltage-dependent than forward transport. Third, electro-genicity is distributed over several reverse transport steps, including intracellular Na~+ binding, reverse translocation, and reverse relocation of the K~+-bound EAAC1. We propose a kinetic model, which is based on a "first-in-first-out" mechanism, suggesting that glutamate association, with its extracellular binding site as well as dissociation from its intracellular binding site, precedes association and dissociation of at least one Na~+ ion. Our model can be used to predict rates of glutamate release from neurons under physiological and pathophysiological conditions.
机译：已知由兴奋性氨基酸载体EAAC1进行的谷氨酸转运是可逆的。因此，谷氨酸可以吸收到细胞中，也可以通过逆向传输从细胞中释放出来，这取决于迁移的离子和迁移的离子的电化学梯度。然而，尚不清楚谷氨酸能从细胞中释放的速度和逆向机理的速度。在这里，我们确定了毫秒级时间分辨率的反向谷氨酸转运的稳态和稳态前动力学。首先，我们的结果表明，谷氨酸和Na〜+依次从其胞质结合位点解离，谷氨酸首先解离，然后是三个共转运的Na〜+离子。其次，谷氨酸转运的动力学很大程度上取决于转运方向，反向转运比正向转运更快，但对电压的依赖性较小。第三，电原性分布在几个反向转运步骤中，包括细胞内Na +结合，反向转运以及与K +结合的EAAC1的反向转运。我们提出了一种基于“先进先出”机制的动力学模型，表明谷氨酸缔合及其胞外结合位点以及从其胞内结合位点的解离先于至少一个的缔合和解离Na〜+离子我们的模型可用于预测生理和病理生理条件下神经元释放谷氨酸的速率。

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