# Understanding GABAA receptor protein folding and misfolding

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2024 · $510,593

## Abstract

Project Description
 Loss of function of gamma-aminobutyric acid type A (GABAA) receptors is one prominent cause of
genetic epilepsies since they are the primary inhibitory ion channels to maintain the excitation-inhibition
balance in the mammalian central nervous system. Currently, hundreds of clinical variants have been
identified in GABAA receptor subunits, causing their functional defects. Despite the development of
numerous anti-seizure drugs, about one-third of epilepsy patients are resistant to current drug
treatment, and many of them have genetic causes. Therefore, there is an urgent need to understand
the molecular mechanism for the loss of function of pathogenic GABAA receptors as well as to develop
a new therapeutic strategy to correct their function. It has been recognized that reduced surface
trafficking of GABAA receptor variants is one major molecular mechanism for their loss of function. To
reach the plasma membrane to carry out their function, GABAA receptor subunits need to fold and
assemble into pentameric receptors in the endoplasmic reticulum (ER). Many epilepsy-causing GABAA
receptor variants predispose them to protein misfolding in the ER and thus excessive protein
degradation. Recently, we showed that we can correct the function of such variants by restoring their
trafficking to the plasma membrane. Therefore, the overall objective of this proposal is to understand
how cellular degradation pathways remove misfolding-prone GABAA receptor variants; furthermore, we
hypothesize that we can correct the folding of these pathogenic variants to enhance their surface
trafficking and thus function, as a novel strategy to treat genetic epilepsies. Here, in Specific Aim 1, we
will characterize the cellular degradation pathways that remove misfolding-prone GABAA receptor
clinical variants. In Specific Aim 2, we will elucidate a coordinated folding pathway that directs the
protein folding of GABAA receptors in the ER. In Specific Aim 3, we will use small molecules to correct
the folding and thus function of misfolding-prone GABAA receptor clinical variants.

## Key facts

- **NIH application ID:** 10850796
- **Project number:** 5R01NS105789-07
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Tingwei Mu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $510,593
- **Award type:** 5
- **Project period:** 2023-06-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10850796

## Citation

> US National Institutes of Health, RePORTER application 10850796, Understanding GABAA receptor protein folding and misfolding (5R01NS105789-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10850796. Licensed CC0.

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