Journal Article

FZJ-2017-07229

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Impaired K+ binding to glial glutamate transporter EAAT1 in migraine

Kovermann, P.FZJ* ; Hessel, M. ; Kortzak, D.FZJ* ; Jen, J. C. ; Koch, J. ; Fahlke, C.FZJ* ; Freilinger, T. (Corresponding author)

2017
Nature Publishing Group London

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Please use a persistent id in citations: http://hdl.handle.net/2128/15700  doi:10.1038/s41598-017-14176-4

Abstract: SLC1A3 encodes the glial glutamate transporter hEAAT1, which removes glutamate from the synaptic cleft via stoichiometrically coupled Na+-K+-H+-glutamate transport. In a young man with migraine with aura including hemiplegia, we identified a novel SLC1A3 mutation that predicts the substitution of a conserved threonine by proline at position 387 (T387P) in hEAAT1. To evaluate the functional effects of the novel variant, we expressed the wildtype or mutant hEAAT1 in mammalian cells and performed whole-cell patch clamp, fast substrate application, and biochemical analyses. T387P diminishes hEAAT1 glutamate uptake rates and reduces the number of hEAAT1 in the surface membrane. Whereas hEAAT1 anion currents display normal ligand and voltage dependence in cells internally dialyzed with Na+-based solution, no anion currents were observed with internal K+. Fast substrate application demonstrated that T387P abolishes K+-bound retranslocation. Our finding expands the phenotypic spectrum of genetic variation in SLC1A3 and highlights impaired K+ binding to hEAAT1 as a novel mechanism of glutamate transport dysfunction in human disease.

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Contributing Institute(s):

1. Zelluläre Biophysik (ICS-4)

Research Program(s):

1. 553 - Physical Basis of Diseases (POF3-553) (POF3-553)

Appears in the scientific report 2017

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