Effects of the γ2 K289M mutation on the structure and function of GABA Type A Receptors: Insights from molecular dynamics simulations
Research Scientist III, Analytical R & D, Amneal Pharmaceuticals, NJ, USA.
Research Article
World Journal of Biological and Pharmaceutical Research, 2022, 02(01), 030-055.
Article DOI: 10.53346/wjbpr.2022.2.1.0023
Publication history:
Received on 10 January 2022; revised on 28 January 2022; accepted on 30 January 2022
Abstract:
Pentameric ligand-gated ion channels (pLGICs), including GABA type A receptors (GABAARs), play crucial roles in neuronal signaling through their ability to mediate inhibitory neurotransmission. Despite the significant sequence variation among pLGIC subunits, few single nucleotide polymorphisms (SNPs) occur in coding regions, particularly for receptors critical to maintaining neural excitability. The naturally occurring mutation 
2 K289M, linked to generalized epilepsy and febrile seizures, exhibits reduced GABA-evoked current amplitudes and altered receptor kinetics. In this study, we employed molecular dynamics simulations to investigate the structural and functional impacts of the K289M mutation at varying temperatures (300K and 315K). Our findings indicate that the mutation leads to a narrowed pore in the receptor, significantly increasing the energetic barrier for chloride ion conduction, particularly at elevated temperatures. Notably, we observed that the K289M mutation disrupts electrostatic interactions that stabilize the wild-type receptor, suggesting a critical role for charge repulsion in maintaining channel integrity. This research enhances our understanding of the molecular mechanisms underlying epilepsy-associated mutations in GABAARs and underscores the importance of temperature-dependent effects on receptor dynamics.
2 K289M, linked to generalized epilepsy and febrile seizures, exhibits reduced GABA-evoked current amplitudes and altered receptor kinetics. In this study, we employed molecular dynamics simulations to investigate the structural and functional impacts of the K289M mutation at varying temperatures (300K and 315K). Our findings indicate that the mutation leads to a narrowed pore in the receptor, significantly increasing the energetic barrier for chloride ion conduction, particularly at elevated temperatures. Notably, we observed that the K289M mutation disrupts electrostatic interactions that stabilize the wild-type receptor, suggesting a critical role for charge repulsion in maintaining channel integrity. This research enhances our understanding of the molecular mechanisms underlying epilepsy-associated mutations in GABAARs and underscores the importance of temperature-dependent effects on receptor dynamics.Keywords:
GABA Type A Receptors;γ2 K289M Mutation; Pentameric Ligand-Gated Ion Channels (pLGICs); Generalized Epilepsy and Febrile Seizures Plus (GEFS+); Epilepsy-Associated Mutations; Adaptive Biasing Force (ABF) Calculations; Thermodynamic Effects on Ion Channels; WTreceptors
Full text article in PDF:
Copyright information:
Copyright © 2022 Author(s) retain the copyright of this article. This article is published under the terms of the Creative Commons Attribution Liscense 4.0