Proteostasis Regulators Restore Function of Epilepsy-Associated GABAA Receptors

Cell Chem Biol. 2021 Jan 21;28(1):46-59.e7. doi: 10.1016/j.chembiol.2020.08.012. Epub 2020 Sep 3.

Abstract

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 (GABAA) 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 GABAA 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 GABAA receptors.

Keywords: ERAD; GABA(A) receptors; assembly; chaperone; epilepsy; folding; misfolding; proteostasis; trafficking.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Dihydroergocristine / pharmacology*
  • Dinoprost / pharmacology*
  • Endoplasmic Reticulum-Associated Degradation / drug effects
  • Epilepsy / drug therapy*
  • Epilepsy / metabolism
  • Female
  • Humans
  • Male
  • Proteostasis / drug effects*
  • Receptors, GABA-A / genetics
  • Receptors, GABA-A / metabolism*

Substances

  • Receptors, GABA-A
  • Dihydroergocristine
  • Dinoprost