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Subunit stoichiometry and arrangement in a heteromeric glutamate-gated chloride channel.


ABSTRACT: The invertebrate glutamate-gated chloride-selective receptors (GluClRs) are ion channels serving as targets for ivermectin (IVM), a broad-spectrum anthelmintic drug used to treat human parasitic diseases like river blindness and lymphatic filariasis. The native GluClR is a heteropentamer consisting of ? and ? subunit types, with yet unknown subunit stoichiometry and arrangement. Based on the recent crystal structure of a homomeric GluCl?R, we introduced mutations at the intersubunit interfaces where Glu (the neurotransmitter) binds. By electrophysiological characterization of these mutants, we found heteromeric assemblies with two equivalent Glu-binding sites at ?/? intersubunit interfaces, where the GluCl? and GluCl? subunits, respectively, contribute the "principal" and "complementary" components of the putative Glu-binding pockets. We identified a mutation in the IVM-binding site (far away from the Glu-binding sites), which significantly increased the sensitivity of the heteromeric mutant receptor to both Glu and IVM, and improved the receptor subunits' cooperativity. We further characterized this heteromeric GluClR mutant as a receptor having a third Glu-binding site at an ?/? intersubunit interface. Altogether, our data unveil heteromeric GluClR assemblies having three ? and two ? subunits arranged in a counterclockwise ?-?-?-?-? fashion, as viewed from the extracellular side, with either two or three Glu-binding site interfaces.

SUBMITTER: Degani-Katzav N 

PROVIDER: S-EPMC4747773 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Subunit stoichiometry and arrangement in a heteromeric glutamate-gated chloride channel.

Degani-Katzav Nurit N   Gortler Revital R   Gorodetzki Lilach L   Paas Yoav Y  

Proceedings of the National Academy of Sciences of the United States of America 20160120 5


The invertebrate glutamate-gated chloride-selective receptors (GluClRs) are ion channels serving as targets for ivermectin (IVM), a broad-spectrum anthelmintic drug used to treat human parasitic diseases like river blindness and lymphatic filariasis. The native GluClR is a heteropentamer consisting of α and β subunit types, with yet unknown subunit stoichiometry and arrangement. Based on the recent crystal structure of a homomeric GluClαR, we introduced mutations at the intersubunit interfaces w  ...[more]

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