Journal Article

FZJ-2022-00049

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Mutations associated with epileptic encephalopathy modify EAAT2 anion channel function

Kovermann, P. (Corresponding author)FZJ* ; Kolobkova, Y. ; Franzen, A.FZJ* ; Fahlke, C.FZJ*

2022
Wiley-Blackwell Oxford [u.a.]

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Please use a persistent id in citations: http://hdl.handle.net/2128/31300  doi:10.1111/epi.17154

Abstract: ObjectiveMutations 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.

Note: Funding information: German Ministry of Education and Research, Grant Number: 01GM19007Early View: Onlinefirst

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Contributing Institute(s):

1. Molekular- und Zellphysiologie (IBI-1)

Research Program(s):

1. 5244 - Information Processing in Neuronal Networks (POF4-524) (POF4-524)

Appears in the scientific report 2022

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