The endoplasmic reticulum membrane complex promotes proteostasis of GABAA receptors

Angela L Whittsette; Ya-Juan Wang; Ting-Wei Mu

doi:10.1016/j.isci.2022.104754

The endoplasmic reticulum membrane complex promotes proteostasis of GABA_A receptors

iScience. 2022 Jul 13;25(8):104754. doi: 10.1016/j.isci.2022.104754. eCollection 2022 Aug 19.

Authors

Angela L Whittsette¹, Ya-Juan Wang¹, Ting-Wei Mu¹

Affiliation

¹ Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA.

Abstract

The endoplasmic reticulum membrane complex (EMC) plays a critical role in the biogenesis of tail-anchored proteins and a subset of multi-pass membrane proteins in the endoplasmic reticulum (ER). However, because of nearly exclusive expression of neurotransmitter-gated ion channels in the central nervous system (CNS), the role of the EMC in their biogenesis is not well understood. In this study, we demonstrated that the EMC positively regulates the surface trafficking and thus function of endogenous γ-aminobutyric acid type A (GABA_A) receptors, the primary inhibitory ion channels in the mammalian brain. Moreover, among ten EMC subunits, EMC3 and EMC6 have the most prominent effect, and overexpression of EMC3 or EMC6 is sufficient to restore the function of epilepsy-associated GABA_A receptor variants. In addition, EMC3 and EMC6 demonstrate endogenous interactions with major neuroreceptors, which depends on their transmembrane domains, suggesting a general role of the EMC in the biogenesis of neuroreceptors.

Keywords: Biological sciences; Cell biology; Molecular biology; Molecular neuroscience; Neuroscience.

Abstract

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