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@ARTICLE{Kovermann:838660,
author = {Kovermann, Peter and Hessel, Margarita and Kortzak, Daniel
and Jen, Joanna C. and Koch, Johannes and Fahlke, Christoph
and Freilinger, Tobias},
title = {{I}mpaired {K}+ binding to glial glutamate transporter
{EAAT}1 in migraine},
journal = {Scientific reports},
volume = {7},
number = {1},
issn = {2045-2322},
address = {London},
publisher = {Nature Publishing Group},
reportid = {FZJ-2017-07229},
pages = {13913},
year = {2017},
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.},
cin = {ICS-4},
ddc = {000},
cid = {I:(DE-Juel1)ICS-4-20110106},
pnm = {553 - Physical Basis of Diseases (POF3-553)},
pid = {G:(DE-HGF)POF3-553},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:29066757},
UT = {WOS:000413597800030},
doi = {10.1038/s41598-017-14176-4},
url = {https://juser.fz-juelich.de/record/838660},
}