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• W2129942459 abstract "pLGICs (pentameric ligand-gated ion channels) are a family of structurally homologous cation and anion channels involved in neurotransmission. Cation-selective members of the pLGIC family are typically inhibited by general anaesthetics, whereas anion-selective members are potentiated. GLIC is a prokaryotic cation pLGIC and can be inhibited by clinical concentrations of general anaesthetics. The introduction of three mutations, Y221A (Y-3′A), E222P (E-2′P) and N224R (N0′R), at the selectivity filter and one, A237T (A13′T), at the hydrophobic gate, converted GLIC into an anion channel. The mutated GLIC (GLIC4) became insensitive to the anaesthetics propofol and etomidate, as well as the channel blocker picrotoxin. MD (molecular dynamics) simulations revealed changes in the structure and dynamics of GLIC4 in comparison with GLIC, particularly in the tilting angles of the pore-lining helix [TM2 (transmembrane helix 2)] that consequently resulted in different pore radius and hydration profiles. Propofol binding to an intra-subunit site of GLIC shifted the tilting angles of TM2 towards closure at the hydrophobic gate region, consistent with propofol inhibition of GLIC. In contrast, the pore of GLIC4 was much more resilient to perturbation from propofol binding. The present study underscores the importance of pore dynamics and conformation to anaesthetic effects on channel functions." @default.
• W2129942459 created "2016-06-24" @default.
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• W2129942459 date "2012-12-07" @default.
• W2129942459 modified "2023-09-25" @default.
• W2129942459 title "Reversal of ion-charge selectivity renders the pentameric ligand-gated ion channel GLIC insensitive to anaesthetics" @default.
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• W2129942459 doi "https://doi.org/10.1042/bj20121072" @default.
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