Dataset Information

Principles of activation and permeation in an anion-selective Cys-loop receptor.

ABSTRACT: Fast inhibitory neurotransmission is essential for nervous system function and is mediated by binding of inhibitory neurotransmitters to receptors of the Cys-loop family embedded in the membranes of neurons. Neurotransmitter binding triggers a conformational change in the receptor, opening an intrinsic chloride channel and thereby dampening neuronal excitability. Here we present the first three-dimensional structure, to our knowledge, of an inhibitory anion-selective Cys-loop receptor, the homopentameric Caenorhabditis elegans glutamate-gated chloride channel ? (GluCl), at 3.3?Å resolution. The X-ray structure of the GluCl-Fab complex was determined with the allosteric agonist ivermectin and in additional structures with the endogenous neurotransmitter L-glutamate and the open-channel blocker picrotoxin. Ivermectin, used to treat river blindness, binds in the transmembrane domain of the receptor and stabilizes an open-pore conformation. Glutamate binds in the classical agonist site at subunit interfaces, and picrotoxin directly occludes the pore near its cytosolic base. GluCl provides a framework for understanding mechanisms of fast inhibitory neurotransmission and allosteric modulation of Cys-loop receptors.

SUBMITTER: Hibbs RE

PROVIDER: S-EPMC3160419 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Principles of activation and permeation in an anion-selective Cys-loop receptor.

Hibbs Ryan E RE Gouaux Eric E

Nature 20110515 7349

Fast inhibitory neurotransmission is essential for nervous system function and is mediated by binding of inhibitory neurotransmitters to receptors of the Cys-loop family embedded in the membranes of neurons. Neurotransmitter binding triggers a conformational change in the receptor, opening an intrinsic chloride channel and thereby dampening neuronal excitability. Here we present the first three-dimensional structure, to our knowledge, of an inhibitory anion-selective Cys-loop receptor, the homop ...[more]

PMID: 21572436

Similar Datasets

Project description:Ivermectin is an anthelmintic drug that works by inhibiting neuronal activity and muscular contractility in arthropods and nematodes. It works by activating glutamate-gated chloride channels (GluClRs) at nanomolar concentrations. These receptors, found exclusively in invertebrates, belong to the pentameric Cys-loop receptor family of ligand-gated ion channels (LGICs). Higher (micromolar) concentrations of ivermectin also activate or modulate vertebrate Cys-loop receptors, including the excitatory nicotinic and the inhibitory GABA type-A and glycine receptors (GlyRs). An X-ray crystal structure of ivermectin complexed with the C. elegans ? GluClR demonstrated that ivermectin binds to the transmembrane domain in a cleft at the interface of adjacent subunits. It also identified three hydrogen bonds thought to attach ivermectin to its site. Site-directed mutagenesis and voltage-clamp electrophysiology have also been employed to probe the binding site for ivermectin in ?1 GlyRs. These have raised doubts as to whether the hydrogen bonds are essential for high ivermectin potency. Due to its lipophilic nature, it is likely that ivermectin accumulates in the membrane and binds reversibly (i.e., weakly) to its site. Several lines of evidence suggest that ivermectin opens the channel pore via a structural change distinct from that induced by the neurotransmitter agonist. Conformational changes occurring at locations distant from the pore can be probed using voltage-clamp fluorometry (VCF), a technique which involves quantitating agonist-induced fluorescence changes from environmentally sensitive fluorophores covalently attached to receptor domains of interest. This technique has demonstrated that ivermectin induces a global conformational change that propagates from the transmembrane domain to the neurotransmitter binding site, thus suggesting a mechanism by which ivermectin potentiates neurotransmitter-gated currents. Together, this information provides new insights into the mechanisms of action of this important drug.

Dataset Information

Principles of activation and permeation in an anion-selective Cys-loop receptor.

Publications

Principles of activation and permeation in an anion-selective Cys-loop receptor.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets