# Understanding GABAA receptor protein folding and misfolding

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2021 · $351,756

## Abstract

Project Description
Proteostasis, an optimal state of the cellular proteome, is constantly challenged by intrinsic stress, such
as inherited misfolding-prone proteins, environment, and aging. 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
corresponding ion channel proteins harboring misfolding-prone mutations. We use gamma-
aminobutyric acid type A (GABAA) receptors, the primary inhibitory neurotransmitter-gated ion channels
in the mammalian central nervous systems, as a representative ion channel, to elucidate their folding
and ERAD pathway in the endoplasmic reticulum (ER). The interaction between GABAA receptors and
a network of proteins in cells is critical to maintain the folding, degradation, trafficking, and thus function
of GABAA receptors. However, the molecular mechanism of maintaining GABAA receptor proteostasis is
not well understood. Idiopathic epilepsy has a strong genetic linkage to loss of function of GABAA
receptors. We focus on studying missense mutations that lead to misfolding, extensive degradation,
and thus loss of function of mutant GABAA receptors. Our long term goal is to perform a detailed
molecular mechanism study to elucidate how the folding, assembly, degradation of GABAA receptors
are regulated in cells and use the principles acquired to correct epilepsy-associated misfolded GABAA
receptors. Here, in Specific Aim 1, we aim to elucidate a coordinated engagement of chaperones and
folding enzymes in directing the folding of GABAA receptors in the ER. In Specific Aim 2, we aim to
determine the ERAD pathway of misfolding-prone mutant GABAA receptors. In Specific Aim 3, we
propose to remodel the ER proteostasis network to correct the misfolding and function of pathogenic
GABAA receptors. This proposed research will provide proof-of-principle cases about restoring
proteostasis to ameliorate genetic epilepsy resulting from GABAA receptor misfolding.

## Key facts

- **NIH application ID:** 10136736
- **Project number:** 5R01NS105789-04
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Tingwei Mu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $351,756
- **Award type:** 5
- **Project period:** 2018-08-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10136736

## Citation

> US National Institutes of Health, RePORTER application 10136736, Understanding GABAA receptor protein folding and misfolding (5R01NS105789-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10136736. Licensed CC0.

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