Mechanisms of anion conduction by coupled glutamate transporters

Jan-Philipp Machtens (Lead / Corresponding author), Daniel Kortzak, Christine Lansche, Ariane Leinenweber, Petra Kilian, Birgit Begemann, Ulrich Zachariae, David Ewers, Bert L. de Groot, Rodolfo Briones, Christoph Fahlke (Lead / Corresponding author)

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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
Original languageEnglish
Pages (from-to)542-553
Number of pages12
JournalCell
Volume160
Issue number3
Early online date29 Jan 2015
DOIs
Publication statusPublished - 29 Jan 2015

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    Machtens, J-P., Kortzak, D., Lansche, C., Leinenweber, A., Kilian, P., Begemann, B., Zachariae, U., Ewers, D., de Groot, B. L., Briones, R., & Fahlke, C. (2015). Mechanisms of anion conduction by coupled glutamate transporters. Cell, 160(3), 542-553. https://doi.org/10.1016/j.cell.2014.12.035