Restoring Epilepsy‐Associated Mutant GABAA Receptor Proteostasis

Abstract

GABAA (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 GABAA 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 GABAA 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 GABAA receptors. Our preliminary result showed that critical ER chaperones, namely BiP and calnexin, interact differently with alpha1 subunit of GABAA receptors. Overexpression of BiP and calnexin increased the expression level of mutant GABAA receptors due to enhanced ER folding capacity. We propose that restoring GABAA receptor proteostasis may provide a novel therapeutic strategy for the amelioration of epilepsy and perhaps other misfolding‐associated channelopathies.