Effects of the γ2 K289M mutation on the structure and function of GABA Type A Receptors: Insights from molecular dynamics simulations

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.