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

Ryan E. Hibbs, Eric Gouaux

Research output: Contribution to journalArticle

658 Citations (Scopus)

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 α (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.

Original languageEnglish (US)
Pages (from-to)54-60
Number of pages7
JournalNature
Volume474
Issue number7349
DOIs
StatePublished - Jun 2 2011

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Cysteine Loop Ligand-Gated Ion Channel Receptors
Anions
Ivermectin
Picrotoxin
Synaptic Transmission
Neurotransmitter Agents
Glutamic Acid
Ocular Onchocerciasis
Chloride Channels
Neurotransmitter Receptor
Caenorhabditis elegans
Nervous System
X-Rays
Neurons
Membranes
glutamate-gated chloride channels

ASJC Scopus subject areas

  • General

Cite this

Principles of activation and permeation in an anion-selective Cys-loop receptor. / Hibbs, Ryan E.; Gouaux, Eric.

In: Nature, Vol. 474, No. 7349, 02.06.2011, p. 54-60.

Research output: Contribution to journalArticle

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