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  Mechanisms of anion conduction by coupled glutamate transporters.

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.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0024-B3BB-0 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0029-6C01-C
Genre: Journal Article

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 Creators:
Machtens, J. P.1, Author              
Kortzak, D., Author
Lansche, C., Author
Leinenweber, A., Author
Kilian, P., Author
Begemann, B., Author
Zachariae, U., Author
Ewers, D., Author
de Groot, B. L.1, Author              
Briones, R.1, Author              
Fahlke, C., Author
Affiliations:
1Research Group of Computational Biomolecular Dynamics, MPI for biophysical chemistry, Max Planck Society, ou_578573              

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 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.

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Language(s): eng - English
 Dates: 2015-01-29
 Publication Status: Published in print
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 Rev. Method: Peer
 Identifiers: DOI: 10.1016/j.cell.2014.12.035
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Title: Cell
Source Genre: Journal
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Pages: - Volume / Issue: 160 (3) Sequence Number: - Start / End Page: 542 - 553 Identifier: -