Kanai Yoshikatsu, Hediger Matthias A
Department of Pharmacology and Toxicology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, 181-8611, Tokyo, Japan.
Pflugers Arch. 2004 Feb;447(5):469-79. doi: 10.1007/s00424-003-1146-4. Epub 2003 Oct 7.
The solute carrier family 1 (SLC1) includes five high-affinity glutamate transporters, EAAC1, GLT-1, GLAST, EAAT4 and EAAT5 (SLC1A1, SLC1A2, SLC1A3, SLC1A6, and SLC1A7, respectively) as well as the two neutral amino acid transporters, ASCT1 and ASCT2 (SLC1A4 and ALC1A5, respectively). Although each of these transporters have similar predicted structures, they exhibit distinct functional properties which are variations of a common transport mechanism. The high-affinity glutamate transporters mediate transport of l-Glu, l-Asp and d-Asp, accompanied by the cotransport of 3 Na(+) and 1 H(+), and the countertransport of 1 K(+), whereas ASC transporters mediate Na(+)-dependent exchange of small neutral amino acids such as Ala, Ser, Cys and Thr. The unique coupling of the glutamate transporters allows uphill transport of glutamate into cells against a concentration gradient. This feature plays a crucial role in protecting neurons against glutamate excitotoxicity in the central nervous system. During pathological conditions, such as brain ischemia (e.g. after a stroke), however, glutamate exit can occur due to "reversed glutamate transport", which is caused by a reversal of the electrochemical gradients of the coupling ions. Selective inhibition of the neuronal glutamate transporter EAAC1 (SLC1A1) may be of therapeutic interest to block glutamate release from neurons during ischemia. On the other hand, upregulation of the glial glutamate transporter GLT1 (SLC1A2) may help protect motor neurons in patients with amyotrophic lateral sclerosis (ALS), since loss of function of GLT1 has been associated with the pathogenesis of certain forms of ALS.
溶质载体家族1（SLC1）包括五种高亲和力谷氨酸转运体，即EAAC1、GLT - 1、GLAST、EAAT4和EAAT5（分别为SLC1A1、SLC1A2、SLC1A3、SLC1A6和SLC1A7），以及两种中性氨基酸转运体，即ASCT1和ASCT2（分别为SLC1A4和SLC1A5）。尽管这些转运体各自具有相似的预测结构，但它们表现出不同的功能特性，这些特性是一种共同转运机制的变体。高亲和力谷氨酸转运体介导L - 谷氨酸、L - 天冬氨酸和D - 天冬氨酸的转运，同时伴随3个Na⁺和1个H⁺的同向转运以及1个K⁺的反向转运，而ASC转运体介导Na⁺依赖的小中性氨基酸（如丙氨酸、丝氨酸、半胱氨酸和苏氨酸）的交换。谷氨酸转运体独特的偶联方式使得谷氨酸能够逆浓度梯度向细胞内进行上坡转运。这一特性在保护中枢神经系统中的神经元免受谷氨酸兴奋性毒性方面起着至关重要的作用。然而，在诸如脑缺血（如中风后）等病理状态下，由于偶联离子电化学梯度的反转导致“谷氨酸转运逆转”，谷氨酸会发生外流。选择性抑制神经元谷氨酸转运体EAAC1（SLC1A1）可能在治疗上具有重要意义，可在缺血期间阻断神经元释放谷氨酸。另一方面，胶质细胞谷氨酸转运体GLT1（SLC1A2）的上调可能有助于保护肌萎缩侧索硬化症（ALS）患者的运动神经元，因为GLT1功能丧失与某些形式的ALS发病机制有关。
