title: Isoflurane alters the structure and dynamics of GLIC.
abstract: Pentameric ligand-gated ion channels are targets of general anesthetics. Although the search for discrete anesthetic binding sites has achieved some degree of success, little is known regarding how anesthetics work after the events of binding. Using the crystal structures of the bacterial Gloeobacter violaceus pentameric ligand-gated ion channel (GLIC), which is sensitive to a variety of general anesthetics, we performed multiple molecular dynamics simulations in the presence and absence of the general anesthetic isoflurane. Isoflurane bound to several locations within GLIC, including the transmembrane pocket identified crystallographically, the extracellular (EC) domain, and the interface of the EC and transmembrane domains. Isoflurane also entered the channel after the pore was dehydrated in one of the simulations. Isoflurane disrupted the quaternary structure of GLIC, as evidenced in a striking association between the binding and breakage of intersubunit salt bridges in the EC domain. The pore-lining helix experienced lateral and inward radial tilting motion that contributed to the channel closure. Isoflurane binding introduced strong anticorrelated motions between different subunits of GLIC. The demonstrated structural and dynamical modulations by isoflurane aid in the understanding of the underlying mechanism of anesthetic inhibition of GLIC and possibly other homologous pentameric ligand-gated ion channels.
authors: Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors: Dan
authors: D
authors: Willenbring
authors: Lu Tian
authors: LT
authors: Liu
authors: David
authors: D
authors: Mowrey
authors: Yan
authors: Y
authors: Xu
authors: Pei
authors: P
authors: Tang
mesh_terms: D018681:Anesthetics, General / Q000378:metabolism / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000737:chemistry* / Q000378:metabolism*; D001665:Binding Sites; D002462:Cell Membrane / Q000378:metabolism; D000458:Cyanobacteria; D004305:Dose-Response Relationship, Drug; D015640:Ion Channel Gating / Q000187:drug effects; D007473:Ion Channels / Q000737:chemistry* / Q000378:metabolism*; D007530:Isoflurane / Q000378:metabolism / Q000494:pharmacology*; D056004:Molecular Dynamics Simulation; D009068:Movement / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects; D020836:Protein Structure, Quaternary / Q000187:drug effects
chemical_list: D018681:Anesthetics, General; D001426:Bacterial Proteins; D007473:Ion Channels; D007530:Isoflurane