Proteostasis Regulators Restore Function of Epilepsy-Associated GABAA Receptors.
Cell Chem Biol
; 28(1): 46-59.e7, 2021 01 21.
Article
em En
| MEDLINE
| ID: mdl-32888501
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.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Dinoprosta
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Receptores de GABA-A
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Di-Hidroergocristina
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Epilepsia
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Proteostase
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article