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标题：Two serine residues of the glutamate transporter GLT-1 are crucial for coupling the fluxes of sodium and the neurotransmitter
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作者：Yumin Zhang ; Baruch I. Kanner
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：1999
卷号：96
期号：4
页码：1710-1715
DOI：10.1073/pnas.96.4.1710
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：The neurotoxicity of glutamate in the central nervous system is restricted by several (Na+ + K+)-coupled transporters for this neurotransmitter. The astroglial transporter GLT-1 is the only subtype that exhibits high sensitivity to the nontransportable glutamate analogue dihydrokainate. A marked reduction in sensitivity to the blocker is observed when serine residues 440 and 443 are mutated to glycine and glutamine, which, respectively, occupy these positions in the other homologous glutamate transporters. They are located in the ascending limb of the recently identified pore-loop-like structure. Strikingly, mutation of serine-440 to glycine enables not only sodium but also lithium ions to drive net influx of acidic amino acids. Moreover, the efficiency of lithium as a driving ion for glutamate transport depends on the nature of the amino acid residue present at position 443. Mutant transporters containing single cysteines at the position of either serine residue become sensitive to positively as well as negatively charged methanethiosulfonate derivatives. In S440C transporters significant protection against this inhibition is provided both by transportable and nontransportable glutamate analogues, but not by sodium alone. Our observations indicate that the pore-loop-like structure plays a pivotal role in coupling ion and glutamate fluxes and suggest that it is close to the glutamate-binding site.