000904700 001__ 904700
000904700 005__ 20230228125859.0
000904700 0247_ $$2doi$$a10.1111/epi.17154
000904700 0247_ $$2ISSN$$a0013-9580
000904700 0247_ $$2ISSN$$a1528-1167
000904700 0247_ $$2altmetric$$aaltmetric:119938407
000904700 0247_ $$2pmid$$apmid:34961934
000904700 0247_ $$2WOS$$aWOS:000734862800001
000904700 0247_ $$2Handle$$a2128/31300
000904700 037__ $$aFZJ-2022-00049
000904700 082__ $$a610
000904700 1001_ $$0P:(DE-Juel1)156374$$aKovermann, Peter$$b0$$eCorresponding author
000904700 245__ $$aMutations associated with epileptic encephalopathy modify EAAT2 anion channel function
000904700 260__ $$aOxford [u.a.]$$bWiley-Blackwell$$c2022
000904700 3367_ $$2DRIVER$$aarticle
000904700 3367_ $$2DataCite$$aOutput Types/Journal article
000904700 3367_ $$0PUB:(DE-HGF)16$$2PUB:(DE-HGF)$$aJournal Article$$bjournal$$mjournal$$s1643883624_27540
000904700 3367_ $$2BibTeX$$aARTICLE
000904700 3367_ $$2ORCID$$aJOURNAL_ARTICLE
000904700 3367_ $$00$$2EndNote$$aJournal Article
000904700 500__ $$aFunding information: German Ministry of Education and Research, Grant Number: 01GM19007Early View: Onlinefirst
000904700 520__ $$aObjectiveMutations in the gene solute carrier family member 1A2 (SLC1A2) encoding the excitatory amino acid transporter 2 (EAAT2) are associated with severe forms of epileptic encephalopathy. EAAT2 is expressed in glial cells and presynaptic nerve terminals and represents the main l-glutamate uptake carrier in the mammalian brain. It does not only function as a secondary active glutamate transporter, but also as an anion channel. How naturally occurring mutations affect these two transport functions of EAAT2 and how such alterations cause epilepsy is insufficiently understood.MethodsHere we studied the functional consequences of three disease-associated mutations, which predict amino acid exchanges p.Gly82Arg (G82R), p.Leu85Pro (L85P), and p.Pro289Arg (P289R), by heterologous expression in mammalian cells, biochemistry, confocal imaging, and whole-cell patch-clamp recordings of EAAT2 l-glutamate transport and anion current.ResultsG82R and L85P exchange amino acid residues contribute to the formation of the EAAT anion pore. They enlarge the pore diameter sufficiently to permit the passage of l-glutamate and thus function as l-glutamate efflux pathways. The mutation P289R decreases l-glutamate uptake, but increases anion currents despite a lower membrane expression.Significancel-glutamate permeability of the EAAT anion pore is an unexpected functional consequence of naturally occurring single amino acid substitutions. l-glutamate efflux through mutant EAAT2 anion channels will cause glutamate excitotoxicity and neuronal hyperexcitability in affected patients. Antagonists that selectively suppress the EAAT anion channel function could serve as therapeutic agents in the future.
000904700 536__ $$0G:(DE-HGF)POF4-5244$$a5244 - Information Processing in Neuronal Networks (POF4-524)$$cPOF4-524$$fPOF IV$$x0
000904700 588__ $$aDataset connected to CrossRef, Journals: juser.fz-juelich.de
000904700 7001_ $$0P:(DE-Juel1)171438$$aKolobkova, Yulia$$b1
000904700 7001_ $$0P:(DE-Juel1)131923$$aFranzen, Arne$$b2$$ufzj
000904700 7001_ $$0P:(DE-Juel1)136837$$aFahlke, Christoph$$b3
000904700 773__ $$0PERI:(DE-600)2002194-X$$a10.1111/epi.17154$$gp. epi.17154$$n2$$p388-401$$tEpilepsia$$v63$$x0013-9580$$y2022
000904700 8564_ $$uhttps://juser.fz-juelich.de/record/904700/files/Epilepsia%20-%202022%20-%20Kovermann%20-%20Mutations%20associated%20with%20epileptic%20encephalopathy%20modify%20EAAT2%20anion%20channel%20function.pdf$$yOpenAccess
000904700 8767_ $$d2022-12-20$$eHybrid-OA$$jDEAL
000904700 909CO $$ooai:juser.fz-juelich.de:904700$$pdnbdelivery$$popenCost$$pVDB$$pdriver$$pOpenAPC_DEAL$$popen_access$$popenaire
000904700 9101_ $$0I:(DE-588b)5008462-8$$6P:(DE-Juel1)156374$$aForschungszentrum Jülich$$b0$$kFZJ
000904700 9101_ $$0I:(DE-588b)5008462-8$$6P:(DE-Juel1)131923$$aForschungszentrum Jülich$$b2$$kFZJ
000904700 9101_ $$0I:(DE-588b)5008462-8$$6P:(DE-Juel1)136837$$aForschungszentrum Jülich$$b3$$kFZJ
000904700 9131_ $$0G:(DE-HGF)POF4-524$$1G:(DE-HGF)POF4-520$$2G:(DE-HGF)POF4-500$$3G:(DE-HGF)POF4$$4G:(DE-HGF)POF$$9G:(DE-HGF)POF4-5244$$aDE-HGF$$bKey Technologies$$lNatural, Artificial and Cognitive Information Processing$$vMolecular and Cellular Information Processing$$x0
000904700 9141_ $$y2022
000904700 915__ $$0StatID:(DE-HGF)0160$$2StatID$$aDBCoverage$$bEssential Science Indicators$$d2021-02-04
000904700 915__ $$0StatID:(DE-HGF)1190$$2StatID$$aDBCoverage$$bBiological Abstracts$$d2021-02-04
000904700 915__ $$0LIC:(DE-HGF)CCBYNC4$$2HGFVOC$$aCreative Commons Attribution-NonCommercial CC BY-NC 4.0
000904700 915__ $$0StatID:(DE-HGF)3001$$2StatID$$aDEAL Wiley$$d2021-02-04$$wger
000904700 915__ $$0StatID:(DE-HGF)0113$$2StatID$$aWoS$$bScience Citation Index Expanded$$d2021-02-04
000904700 915__ $$0StatID:(DE-HGF)0510$$2StatID$$aOpenAccess
000904700 915__ $$0StatID:(DE-HGF)0200$$2StatID$$aDBCoverage$$bSCOPUS$$d2022-11-25
000904700 915__ $$0StatID:(DE-HGF)0300$$2StatID$$aDBCoverage$$bMedline$$d2022-11-25
000904700 915__ $$0StatID:(DE-HGF)0199$$2StatID$$aDBCoverage$$bClarivate Analytics Master Journal List$$d2022-11-25
000904700 915__ $$0StatID:(DE-HGF)0150$$2StatID$$aDBCoverage$$bWeb of Science Core Collection$$d2022-11-25
000904700 915__ $$0StatID:(DE-HGF)1050$$2StatID$$aDBCoverage$$bBIOSIS Previews$$d2022-11-25
000904700 915__ $$0StatID:(DE-HGF)1110$$2StatID$$aDBCoverage$$bCurrent Contents - Clinical Medicine$$d2022-11-25
000904700 915__ $$0StatID:(DE-HGF)1030$$2StatID$$aDBCoverage$$bCurrent Contents - Life Sciences$$d2022-11-25
000904700 915__ $$0StatID:(DE-HGF)0100$$2StatID$$aJCR$$bEPILEPSIA : 2021$$d2022-11-25
000904700 915__ $$0StatID:(DE-HGF)0600$$2StatID$$aDBCoverage$$bEbsco Academic Search$$d2022-11-25
000904700 915__ $$0StatID:(DE-HGF)0030$$2StatID$$aPeer Review$$bASC$$d2022-11-25
000904700 915__ $$0StatID:(DE-HGF)9905$$2StatID$$aIF >= 5$$bEPILEPSIA : 2021$$d2022-11-25
000904700 915pc $$0PC:(DE-HGF)0000$$2APC$$aAPC keys set
000904700 915pc $$0PC:(DE-HGF)0001$$2APC$$aLocal Funding
000904700 915pc $$0PC:(DE-HGF)0002$$2APC$$aDFG OA Publikationskosten
000904700 915pc $$0PC:(DE-HGF)0120$$2APC$$aDEAL: Wiley 2019
000904700 920__ $$lyes
000904700 9201_ $$0I:(DE-Juel1)IBI-1-20200312$$kIBI-1$$lMolekular- und Zellphysiologie$$x0
000904700 980__ $$ajournal
000904700 980__ $$aVDB
000904700 980__ $$aUNRESTRICTED
000904700 980__ $$aI:(DE-Juel1)IBI-1-20200312
000904700 980__ $$aAPC
000904700 9801_ $$aAPC
000904700 9801_ $$aFullTexts