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Review
. 2015 Sep;72(18):3489-506.
doi: 10.1007/s00018-015-1937-8. Epub 2015 Jun 2.

Glutamate transporter EAAT2: regulation, function, and potential as a therapeutic target for neurological and psychiatric disease

Kou Takahashi  1 , Joshua B Foster, Chien-Liang Glenn Lin
Affiliations
Review

Glutamate transporter EAAT2: regulation, function, and potential as a therapeutic target for neurological and psychiatric disease

Kou Takahashi et al. Cell Mol Life Sci. 2015 Sep.

Abstract

Glutamate is the predominant excitatory neurotransmitter in the central nervous system. Excitatory amino acid transporter 2 (EAAT2) is primarily responsible for clearance of extracellular glutamate to prevent neuronal excitotoxicity and hyperexcitability. EAAT2 plays a critical role in regulation of synaptic activity and plasticity. In addition, EAAT2 has been implicated in the pathogenesis of many central nervous system disorders. In this review, we summarize current understanding of EAAT2, including structure, pharmacology, physiology, and functions, as well as disease relevancy, such as in stroke, Parkinson's disease, epilepsy, amyotrophic lateral sclerosis, Alzheimer's disease, major depressive disorder, and addiction. A large number of studies have demonstrated that up-regulation of EAAT2 protein provides significant beneficial effects in many disease models suggesting EAAT2 activation is a promising therapeutic approach. Several EAAT2 activators have been identified. Further understanding of EAAT2 regulatory mechanisms could improve development of drug-like compounds that spatiotemporally regulate EAAT2.

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Figures

Fig. 1
Fig. 1
Structure of substrate, activators, and inhibitors
Fig. 2
Fig. 2
Transport mechanism and structure of glutamate transporter. There are eight transmembrane (TM) domains and two helical hairpins (HP1 and HP2). a The topology model of an archaeal homolog of the EAATs from pyrococcus horikoshii, GltPh, is shown. TM 1, 2, 4, and 5 are included in the scaffold domain (trimerization domain) while TM 3, 6, 7, and 8, and HP1-2 are included in the core transport domain. b The stoichiometry of transport. EAATs exhibit influx of glutamate/aspartate (Glu), 3 Na+ and 1 H+, and outflux of 1 K+. GltPh utilizes influx of aspartate (Asp) and 3 Na+. c The hypothetical transport mechanism of GltPh. Reyes et al. proposed that the tips HP1 and HP2 contribute to substrate binding and transport [85] and are accompanied with rotation of the core transport domain (red). The trimerization domain is indicated in blue. d The bowl-shaped structure of the GltPh trimer. Each subunit is represented as blue, green, and white. The crystal structure is based on GltPh binding with TBOA (PBD 2NWW, http://www.rcsb.org/pdb/home/home.do)
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