Impaired K+ binding to glial glutamate transporter EAAT1 in migraine

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 substitut...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Peter Kovermann, Margarita Hessel, Daniel Kortzak, Joanna C. Jen, Johannes Koch, Christoph Fahlke, Tobias Freilinger
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/29823721443a4019960ff51246f63d0e
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:29823721443a4019960ff51246f63d0e
record_format	dspace
spelling	oai:doaj.org-article:29823721443a4019960ff51246f63d0e2021-12-02T11:40:12ZImpaired K+ binding to glial glutamate transporter EAAT1 in migraine10.1038/s41598-017-14176-42045-2322https://doaj.org/article/29823721443a4019960ff51246f63d0e2017-10-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-14176-4https://doaj.org/toc/2045-2322Abstract 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.Peter KovermannMargarita HesselDaniel KortzakJoanna C. JenJohannes KochChristoph FahlkeTobias FreilingerNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-10 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Peter Kovermann Margarita Hessel Daniel Kortzak Joanna C. Jen Johannes Koch Christoph Fahlke Tobias Freilinger Impaired K+ binding to glial glutamate transporter EAAT1 in migraine
description	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.
format	article
author	Peter Kovermann Margarita Hessel Daniel Kortzak Joanna C. Jen Johannes Koch Christoph Fahlke Tobias Freilinger
author_facet	Peter Kovermann Margarita Hessel Daniel Kortzak Joanna C. Jen Johannes Koch Christoph Fahlke Tobias Freilinger
author_sort	Peter Kovermann
title	Impaired K+ binding to glial glutamate transporter EAAT1 in migraine
title_short	Impaired K+ binding to glial glutamate transporter EAAT1 in migraine
title_full	Impaired K+ binding to glial glutamate transporter EAAT1 in migraine
title_fullStr	Impaired K+ binding to glial glutamate transporter EAAT1 in migraine
title_full_unstemmed	Impaired K+ binding to glial glutamate transporter EAAT1 in migraine
title_sort	impaired k+ binding to glial glutamate transporter eaat1 in migraine
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/29823721443a4019960ff51246f63d0e
work_keys_str_mv	AT peterkovermann impairedkbindingtoglialglutamatetransportereaat1inmigraine AT margaritahessel impairedkbindingtoglialglutamatetransportereaat1inmigraine AT danielkortzak impairedkbindingtoglialglutamatetransportereaat1inmigraine AT joannacjen impairedkbindingtoglialglutamatetransportereaat1inmigraine AT johanneskoch impairedkbindingtoglialglutamatetransportereaat1inmigraine AT christophfahlke impairedkbindingtoglialglutamatetransportereaat1inmigraine AT tobiasfreilinger impairedkbindingtoglialglutamatetransportereaat1inmigraine
_version_	1718395691628232704

Impaired K+ binding to glial glutamate transporter EAAT1 in migraine

Ejemplares similares