Zeineb Fourati, Howard R, Lindahl E and Delarue M
Pasteur Institute, France
Posters & Accepted Abstracts: Biochem Mol biol J
Allosteric modulation by general anesthetics, such as propofol, is a key pharmacological property of many pentameric ligand-gated ion channels (pLGICs) with critical implications for receptor biophysics and drug development. Functional studies have revealed conserved sites of both positive and negative modulation by anesthetics in this channel family, but mechanistic interpretations have been limited by the scope and resolution of structural data. The prokaryotic homolog GLIC has been shown a useful model system that recapitulates functional modulation of human ion channels, and enables structure determination both in apparent conducting and non-conducting states. Here, we provide crystallographic and electrophysiological evidence that anesthetics either inhibit or potentiate GLIC function by binding in the ion pore or in several sub regions of a key transmembrane cavity, respectively. Binding to each region evidently stabilizes a different functional state of the receptor, thus offering an integrated, multiple site allosteric model of pLGIC modulation by general anaesthetics.
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