The N-terminus of the norepinephrine transporter regulates the magnitude and selectivity of the transporter-associated leak current
The N-terminus of the norepinephrine transporter regulates the magnitude and selectivity of the transporter-associated leak current
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DOI：
10.1016/j.neuropharm.2005.09.012
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发表时间：
2006-03-01
影响因子：
4.7
通讯作者：
Galli, A
中科院分区：
文献类型：
--
作者：
Binda, F;Lute, BJ;Galli, A
去甲肾上腺素（NE）转运体（NET）介导NE从突触间隙的移除，是抗抑郁药、安非他明和可卡因的主要靶点。先前，我们已经证明syntaxin 1A （SYN 1A）支持人类NET （hNET）细胞表面表达，hNET/SYN 1A相互作用由hNET n端直接介导，并且hNET/SYN 1A关联限制了底物诱导的hNET相关电流[Sung， U, Apparsundaram， S., Galli， A., Kahlig, k.m., Savchenko， V., Schroeter， S., Quick, m.w., Blakely, rd ., 2003]。syntaxin 1A与抗抑郁药敏感的去甲肾上腺素转运体的调节相互作用建立儿茶酚胺的清除能力。[j].中国生物医学工程学报，2009,33(2):387 - 398。这些数据提出了一种可能性，即hNET n端及其与SYN 1A的潜在相互作用可能调节其他hNET电导状态，包括hNET介导的泄漏电流。重要的是，对于单胺转运体，泄漏电导已被证明在调节细胞膜电位和可能的神经元兴奋性方面发挥关键作用[Quick， m.w., 2003]。调节哺乳动物血清素转运体的传导状态。[j].中国生物医学工程学报，2016,33(5):537-549。在这里，我们证明了在NET n端删除SYN 1A的结合域可以增强NET介导的泄漏电流，以及在特定细胞内离子组成下对Cl-渗透的选择性。此外，我们发现NET n端协调细胞内Na+和Cl-调节泄漏电导的能力。这些数据表明，NET的n端调节和定义了NET介导的泄漏电流的离子特异性。(c) 2005 Elsevier Ltd版权所有。
The norepinephrine (NE) transporter (NET) mediates the removal of NE from synaptic spaces and is a major target for antidepressants, amphetamine and cocaine. Previously, we have shown that syntaxin 1A (SYN 1A) supports human NET (hNET) cell surface expression, that hNET/SYN 1A interactions are direct and mediated by the hNET N-terminus, and that the hNET/SYN 1A association limits substrate-induced hNET-associated currents [Sung, U., Apparsundaram, S., Galli, A., Kahlig, K.M., Savchenko, V., Schroeter, S., Quick, M.W., Blakely, R.D., 2003. A regulated interaction of syntaxin 1A with the antidepressant-sensitive norepinephrine transporter establishes catecholamine, clearance capacity. J. Neurosci. 23, 1697-1709]. These data raise the possibility that the hNET N-terminus, and potentially its interaction with SYN 1A, might regulate other hNET conductance states, including the hNET-mediated leak current. Importantly for monoamine transporters, the leak conductance has been shown to play a critical role in regulating cell membrane potential and possibly neuronal excitability [Quick, M.W., 2003. Regulating the conducting states of a mammalian serotonin transporter. Neuron 40, 537-549]. Here we demonstrate that deletion of the binding domain for SYN 1A in the NET N-terminus robustly enhances the NET-mediated leak current as well as its selectivity for Cl- permeation under particular intracellular ionic compositions. In addition, we show that the NET N-terminus coordinates the ability of intracellular Na+ and Cl- to regulate the leak conductance. These data suggest that the NET N-terminus regulates and defines the ionic specificity of the NET-mediated leak current. (c) 2005 Elsevier Ltd. All rights reserved.