Abstract
Cys-loop receptors constitute a superfamily of pentameric ligand-gated ion channels (pLGICs), including receptors for acetylcholine, serotonin, glycine and γ-aminobutyric acid. Several bacterial homologues have been identified that are excellent models for understanding allosteric binding of alcohols and anesthetics in human Cys-loop receptors. Recently, we showed that a single point mutation on a prokaryotic homologue (GLIC) could transform it from a channel weakly potentiated by ethanol into a highly ethanol-sensitive channel. Here, we have employed molecular simulations to study ethanol binding to GLIC, and to elucidate the role of the ethanol-enhancing mutation in GLIC modulation. By performing 1-µs simulations with and without ethanol on wild-type and mutated GLIC, we observed spontaneous binding in both intra-subunit and inter-subunit transmembrane cavities. In contrast to the glycine receptor GlyR, in which we previously observed ethanol binding primarily in an inter-subunit cavity, ethanol primarily occupied an intra-subunit cavity in wild-type GLIC. However, the highly ethanol-sensitive GLIC mutation significantly enhanced ethanol binding in the inter-subunit cavity. These results demonstrate dramatic effects of the F(14′)A mutation on the distribution of ligands, and are consistent with a two-site model of pLGIC inhibition and potentiation.
Highlights
Synaptic transmission is one of the most important functions of our nervous system, and modulation of post-synaptic receptors is of tremendous importance to understanding the effects of toxins, neuropharmaceuticals, drugs of abuse, and anesthetics, as well as the physiological basis for consciousness
We previously showed that the mutation F(149)A transforms GLIC into a highly ethanol-sensitive channel that is potentiated by alcohols as large as hexanol [25], more closely approximating the properties of glycine receptors (GlyRs) and GABAARs [4,5]
We further demonstrated by molecular dynamics that the enhanced potentiation of the F(149)A variant correlated with expansion of the inter-subunit cavity [25]
Summary
Synaptic transmission is one of the most important functions of our nervous system, and modulation of post-synaptic receptors is of tremendous importance to understanding the effects of toxins, neuropharmaceuticals, drugs of abuse, and anesthetics, as well as the physiological basis for consciousness. Ethanol affects the central nervous system by interacting with several proteins, in particular post-synaptic ion channel receptors. Several key targets of alcohol modulation fall in the family of Cys-loop receptors (see reviews [1,2]). Cys-loop receptors constitute a family of pentameric ligandgated ion channels (pLGICs). These receptors are activated by a variety of ligands, from which they draw their names: they include the cation-conducting nicotinic acetylcholine receptors (nAChRs) and serotonin-3 receptors, and the anion-conducting glycine receptors (GlyRs) and c-aminobutyric acid-A receptors (GABAARs). In addition to activation by their respective ligands, pLGICs exhibit allosteric modulation by numerous endogenous and exogenous molecules, including alcohols and anesthetics. Alcohols and anesthetics potentiate many anionic channels (GlyRs and most GABAARs [3,4,5]), whereas only shortchain alcohols potentiate nAChRs [6]; longer-chain alcohols and most anesthetics inhibit nAChRs [6], and both types of modulators inhibit the r subtype of GABAARs [7]
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