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Journal Article

Mechanisms of anion conduction by coupled glutamate transporters.

MPS-Authors
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Machtens,  J. P.
Research Group of Computational Biomolecular Dynamics, MPI for biophysical chemistry, Max Planck Society;

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de Groot,  B. L.
Research Group of Computational Biomolecular Dynamics, MPI for biophysical chemistry, Max Planck Society;

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Briones,  R.
Research Group of Computational Biomolecular Dynamics, MPI for biophysical chemistry, Max Planck Society;

Fulltext (public)

2087011.pdf
(Publisher version), 6MB

Supplementary Material (public)

2087011_Suppl_1.pdf
(Supplementary material), 117KB

2087011_Suppl_2.mp4
(Supplementary material), 33MB

2087011_Suppl_3.pdf
(Supplementary material), 15MB

Citation

Machtens, J. P., Kortzak, D., Lansche, C., Leinenweber, A., Kilian, P., Begemann, B., et al. (2015). Mechanisms of anion conduction by coupled glutamate transporters. Cell, 160(3), 542-553. doi:10.1016/j.cell.2014.12.035.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0024-B3BB-0
Abstract
Excitatory amino acid transporters (EAATs) are essential for terminating glutamatergic synaptic transmission. They are not only coupled glutamate/Na(+)/H(+)/K(+) transporters but also function as anion-selective channels. EAAT anion channels regulate neuronal excitability, and gain-of-function mutations in these proteins result in ataxia and epilepsy. We have combined molecular dynamics simulations with fluorescence spectroscopy of the prokaryotic homolog GltPh and patch-clamp recordings of mammalian EAATs to determine how these transporters conduct anions. Whereas outward- and inward-facing GltPh conformations are nonconductive, lateral movement of the glutamate transport domain from intermediate transporter conformations results in formation of an anion-selective conduction pathway. Fluorescence quenching of inserted tryptophan residues indicated the entry of anions into this pathway, and mutations of homologous pore-forming residues had analogous effects on GltPh simulations and EAAT2/EAAT4 measurements of single-channel currents and anion/cation selectivities. These findings provide a mechanistic framework of how neurotransmitter transporters can operate as anion-selective and ligand-gated ion channels.