Proteostasis deficiency in mutated ion channels leads to a variety of ion channel diseases that are caused by excessive endoplasmic reticulum-associated degradation (ERAD) and inefficient membrane trafficking. We investigated proteostasis maintenance of γ-aminobutyric acid type A (GABA_A) receptors, the primary mediators of neuronal inhibition in the mammalian central nervous system. We screened a structurally diverse, Food and Drug Administration-approved drug library and identified dinoprost (DNP) and dihydroergocristine (DHEC) as highly efficacious enhancers of surface expression of four epilepsy-causing trafficking-deficient mutant receptors. Furthermore, DNP and DHEC restore whole-cell and synaptic currents by incorporating mutated subunits into functional receptors. Mechanistic studies revealed that both drugs reduce subunit degradation by attenuating the Grp94/Hrd1/Sel1L/VCP-mediated ERAD pathway and enhance the subunit folding by promoting subunit interactions with major GABA_A receptors-interacting chaperones, BiP and calnexin. In summary, we report that DNP and DHEC remodel the endoplasmic reticulum proteostasis network to restore the functional surface expression of mutant GABA_A receptors.

突变离子通道中的蛋白质稳态缺乏会导致多种离子通道疾病，这些疾病是由过度的内质网相关降解 (ERAD) 和低效的膜运输引起的。我们研究了 γ-氨基丁酸 A 型（GABA _A) 受体，哺乳动物中枢神经系统中神经元抑制的主要介质。我们筛选了一个结构多样、经食品和药物管理局批准的药物库，并确定地诺前列素 (DNP) 和二氢麦角新碱 (DHEC) 是四种引起癫痫的贩运缺陷型突变受体表面表达的高效增强剂。此外，DNP 和 DHEC 通过将突变的亚基整合到功能性受体中来恢复全细胞和突触电流。机理研究表明，这两种药物都通过减弱 Grp94/Hrd1/Sel1L/VCP 介导的 ERAD 途径来减少亚基降解，并通过促进与主要 GABA _{A 的亚基相互作用来增强亚基折叠。}受体相互作用的伴侣，BiP和钙连接蛋白。总之，我们报告 DNP 和 DHEC 重塑内质网蛋白稳态网络以恢复突变 GABA _A受体的功能性表面表达。