Evidence for a third sodium-binding site in glutamate transporters suggests an ion/substrate coupling model.

Proceedings of the National Academy of Sciences of the United States of America
H Peter LarssonSergei Y Noskov

Abstract

Excitatory amino acid transporters (EAATs) remove glutamate from synapses. They maintain an efficient synaptic transmission and prevent glutamate from reaching neurotoxic levels. Glutamate transporters couple the uptake of one glutamate to the cotransport of three sodium ions and one proton and the countertransport of one potassium ion. The molecular mechanism for this coupled uptake of glutamate and its co- and counter-transported ions is not known. In a crystal structure of the bacterial glutamate transporter homolog, GltPh, only two cations are bound to the transporter, and there is no indication of the location of the third sodium site. In experiments using voltage clamp fluorometry and simulations based on molecular dynamics combined with grand canonical Monte Carlo and free energy simulations performed on different isoforms of GltPh as well on a homology model of EAAT3, we sought to locate the third sodium-binding site in EAAT3. Both experiments and computer simulations suggest that T370 and N451 (T314 and N401 in GltPh) form part of the third sodium-binding site. Interestingly, the sodium bound at T370 forms part of the binding site for the amino acid substrate, perhaps explaining both the strict coupling of sodium trans...Continue Reading

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Citations

Nov 19, 2013·Pflügers Archiv : European journal of physiology·Christof GrewerThomas Rauen
May 15, 2013·Structure·Paul J FockeH Peter Larsson
Apr 9, 2013·Nature Structural & Molecular Biology·Nicolas ReyesOlga Boudker
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