Abstract: Proteostasis deficiency in ion channels leads to a variety of ion channel diseases called channelopathies, which are often caused by excessive endoplasmic reticulum-associated degradation (ERAD) and inefficient membrane trafficking of mutant ion channels. We focus on proteostasis maintenance of gamma-aminobutyric acid type A (GABAA) receptors, the primary inhibitory ion channels in the mammalian central nervous system. Numerous epilepsy-associated missense mutations in the receptor subunits predispose them to rapid ERAD, reduce their cell surface expression, and cause loss of their function. We aimed to use small molecules to adapt the proteostasis network in the ER to restore the surface trafficking and function of such mutant receptors. Our screening assay from a structurally diverse FDA-approved drug library identified lead compounds that enhanced the surface expression of a number of trafficking-deficient mutant receptors. Furthermore, patch clamping electrophysiology showed that these lead compounds restored their function on the plasma membrane. Mechanistic studies revealed that they reduced the degradation by attenuating the ERAD pathway. In addition, they enhanced the folding of the mutant subunits by enhancing their interactions with major GABAA receptors-interacting chaperones. Both ERAD inhibition and folding enhancement contributed to the improved ER-to-Golgi trafficking efficiency of the mutant receptors. These compounds hold the promise to be further developed to ameliorate idiopathic epilepsy resulting from excessive GABAA receptor degradation.
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