Abstract
General anesthetics exert their effects on the central nervous system by acting on ion channels, most notably pentameric ligand-gated ion channels. Although numerous studies have focused on pentameric ligand-gated ion channels, the details of anesthetic binding and channel modulation are still debated. A better understanding of the anesthetic mechanism of action is necessary for the development of safer and more efficacious drugs. Herein, we present a computational study identifying two anesthetic binding sites in the transmembrane domain of the Gloeobacter violaceus ligand-gated ion channel (GLIC) channel, characterize the putative binding pathway, and observe structural changes associated with channel function. Molecular simulations of desflurane reveal a binding pathway to GLIC via a membrane-embedded tunnel using an intrasubunit protein lumen as the conduit, an observation that explains the Meyer-Overton hypothesis, or why the lipophilicity of an anesthetic and its potency are generally proportional. Moreover, employing high concentrations of ligand led to the identification of a second transmembrane site (TM2) that inhibits dissociation of anesthetic from the TM1 site and is consistent with the high concentrations of anesthetics required to achieve clinical effects. Finally, asymmetric binding patterns of anesthetic to the channel were found to promote an iris-like conformational change that constricts and dehydrates the ion pore, creating a 13.5 kcal/mol barrier to ion translocation. Together with previous studies, the simulations presented herein demonstrate a novel anesthetic binding site in GLIC that is accessed through a membrane-embedded tunnel and interacts with a previously known site, resulting in conformational changes that produce a non-conductive state of the channel.
Highlights
General anesthetics exert their effects on the central nervous system by acting on ion channels, most notably pentameric ligand-gated ion channels
Contact probabilities computed to quantify the extent of these diffuse interactions largely show even sampling of each residue in the binding region by the anesthetic (Fig. 2c, Table 1), supporting the idea that GLIC lacks a tight binding site that is specific to anesthetics
The questions of where anesthetics bind to ion-permeable channels and how they exert their effects on the dynamics of these channels remains unclear
Summary
General anesthetics exert their effects on the central nervous system by acting on ion channels, most notably pentameric ligand-gated ion channels. It was once generally accepted that anesthetics worked through a nonspecific membrane disruption mechanism [1, 2], that theory has become obsolete, and it is known that most, if not all, anesthetics target ion channels in the nervous system, most notably the Cys-loop family of pentameric ligand-gated ion channels (pLGIC)2 [3,4,5,6] This family of proteins, which acts in response to release of neurotransmitters from the presynaptic terminal, was the target for multiple pharmaceutical agents, including alcohol, barbiturates, and benzodiazepines, in addition to anesthetics [5, 7,8,9,10,11]. Multiple anesthetics are needed to bind each subunit to exert their effects with establishment of an asymmetric ligand occupancy in GLIC leading to conformational changes that result in a non-conductive state
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