Understanding GABAA receptor protein folding and misfolding

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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.