SAHA Enhances Proteostasis of Epilepsy-Associated α1(A322D)β2γ2 GABAA Receptors

GABA(A) receptors are the primary inhibitory ion channels in the mammalian central nervous system. The A322D mutation in the al subunit of GABA(A) receptors is known to result in its degradation and reduce its cell surface expression, leading to loss of GABA(A) receptor function in autosomal dominant juvenile myoclonic epilepsy. Here, we show that SAHA, a FDA-approved drug, increases the transcription of the alpha 1(A322D) subunit, enhances its folding and trafficking posttranslationally, increases its cell surface level, and restores the GABA-induced maximal current in HEK293 cells expressing alpha 1(A322D)132y2 receptors to 10% of that for wild-type receptors. To enhance the trafficking efficiency of the alpha 1(A322D) subunit, SAHA increases the BiP protein level and the interaction between the alpha 1(A322D) subunit and calnexin. SAHA is a drug that enhances epilepsyassociated GABA(A) receptor proteostasis.