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Agonist Selectivity and Ion Permeation in the ?3?4 Ganglionic Nicotinic Receptor.

ABSTRACT: Nicotinic acetylcholine receptors are pentameric ion channels that mediate fast chemical neurotransmission. The ?3?4 nicotinic receptor subtype forms the principal relay between the central and peripheral nervous systems in the autonomic ganglia. This receptor is also expressed focally in brain areas that affect reward circuits and addiction. Here, we present structures of the ?3?4 nicotinic receptor in lipidic and detergent environments, using functional reconstitution to define lipids appropriate for structural analysis. The structures of the receptor in complex with nicotine, as well as the ?3?4-selective ligand AT-1001, complemented by molecular dynamics, suggest principles of agonist selectivity. The structures further reveal much of the architecture of the intracellular domain, where mutagenesis experiments and simulations define residues governing ion conductance.

SUBMITTER: Gharpure A

PROVIDER: S-EPMC6842111 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Agonist Selectivity and Ion Permeation in the α3β4 Ganglionic Nicotinic Receptor.

Gharpure Anant A Teng Jinfeng J Zhuang Yuxuan Y Noviello Colleen M CM Walsh Richard M RM Cabuco Rico R Howard Rebecca J RJ Zaveri Nurulain T NT Lindahl Erik E Hibbs Ryan E RE

Neuron 20190902 3

Nicotinic acetylcholine receptors are pentameric ion channels that mediate fast chemical neurotransmission. The α3β4 nicotinic receptor subtype forms the principal relay between the central and peripheral nervous systems in the autonomic ganglia. This receptor is also expressed focally in brain areas that affect reward circuits and addiction. Here, we present structures of the α3β4 nicotinic receptor in lipidic and detergent environments, using functional reconstitution to define lipids appropri ...[more]

PMID: 31488329

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