Abstract
Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system. After its release from presynaptic nerve terminals, glutamate is quickly removed from the synaptic cleft by excitatory amino acid transporters (EAATs) 1–5, a subfamily of glutamate transporters. The five proteins utilize a complex transport stoichiometry that couples glutamate transport to the symport of three Na+ ions and one H+ in exchange with one K+ to accumulate glutamate against up to 106-fold concentration gradients. They are also anion-selective channels that open and close during transitions along the glutamate transport cycle. EAATs belong to a larger family of secondary-active transporters, the SLC1 family, which also includes purely Na+- or H+-coupled prokaryotic transporters and Na+-dependent neutral amino acid exchangers. In recent years, molecular cloning, heterologous expression, cellular electrophysiology, fluorescence spectroscopy, structural approaches, and molecular simulations have uncovered the molecular mechanisms of coupled transport, substrate selectivity, and anion conduction in EAAT glutamate transporters. Here we review recent findings on EAAT transport mechanisms, with special emphasis on the highly conserved hairpin 2 gate, which has emerged as the central processing unit in many of these functions.
Highlights
Abbreviations channel-like conformation (ChC) Channel-like conformation episodic ataxia type 6 (EA6) Episodic ataxia 6 excitatory amino acid transporters (EAATs) Excitatory amino acid transporter GltPh Glutamate transporter homologue from Pyrococcus horikoshii GltTk Glutamate transporter homologue from Thermococcus kodakarensis IC Intermediate conformation IFC Inward-facing conformation
Baruch described the key features of EAAT function: stereoselective glutamate uptake and the coupling of glutamate transport to the inward movement of at least two N a+, with obligatory K + dependence
Baruchs group reported the isolation of a complementary DNA clone encoding the glial glutamate transporter GLT-1 [7], and Kanai and Hediger reported expression cloning of EAAC1 from rabbit small intestine [8]
Summary
The excitatory amino acid transporters (EAATs) are the predominant glutamate transporters in the mammalian brain [1] They were first studied in detail by Baruch Kanner and colleagues in experiments using radiotracer flux experiments and membrane vesicles from the mammalian brain [2,3,4,5]. In his seminal work, Baruch described the key features of EAAT function: stereoselective glutamate uptake and the coupling of glutamate transport to the inward movement of at least two N a+, with obligatory K + dependence. K+ coupling increases the driving force in cells that have membrane potentials positive to the K+ equilibrium potential
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