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Restoring Epilepsy‐Associated Mutant GABA A Receptor Proteostasis
Author(s) -
Di Xiaojing,
Mu Tingwei
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.lb109
Subject(s) - proteostasis , calnexin , gabaa receptor , receptor , microbiology and biotechnology , gamma aminobutyric acid , endoplasmic reticulum , ion channel , proteome , epilepsy , biology , gabab receptor , juvenile myoclonic epilepsy , endoplasmic reticulum associated protein degradation , protein subunit , chemistry , biochemistry , neuroscience , unfolded protein response , gene , calreticulin
GABA A (γ‐aminobutyric acid type A) receptors are major inhibitory neurotransmitter ligand‐gated ion channels in the mammalian central nervous system. Recently, several mutations in the GABA A receptors were identified to compromise protein folding, subjecting channel proteins to endoplasmic reticulum (ER)‐associated degradation, leading to epilepsy due to loss of channel function. One prominent example is the A322D mutation in the alpha1 subunit of GABA A receptor, resulting in juvenile myoclonic epilepsy. We employed a mass‐spectrometry based proteomics approach to quantify the proteome difference between wild type and alpha1(A322D)beta2gamma2 GABA A receptors. Our preliminary result showed that critical ER chaperones, namely BiP and calnexin, interact differently with alpha1 subunit of GABA A receptors. Overexpression of BiP and calnexin increased the expression level of mutant GABA A receptors due to enhanced ER folding capacity. We propose that restoring GABA A receptor proteostasis may provide a novel therapeutic strategy for the amelioration of epilepsy and perhaps other misfolding‐associated channelopathies.