Molecular interaction of α-conotoxin RgIA with the rat α9α10 nicotinic acetylcholine receptor

Molecular Pharmacology
Layla AzamJ Michael McIntosh

Abstract

The α9α10 nicotinic acetylcholine receptor (nAChR) was first identified in the auditory system, where it mediates synaptic transmission between efferent olivocochlear cholinergic fibers and cochlea hair cells. This receptor gained further attention due to its potential role in chronic pain and breast and lung cancers. We previously showed that α-conotoxin (α-CTx) RgIA, one of the few α9α10 selective ligands identified to date, is 300-fold less potent on human versus rat α9α10 nAChR. This species difference was conferred by only one residue in the (-), rather than (+), binding region of the α9 subunit. In light of this unexpected discovery, we sought to determine other interacting residues with α-CTx RgIA. A previous molecular modeling study, based on the structure of the homologous molluscan acetylcholine-binding protein, predicted that RgIA interacts with three residues on the α9(+) face and two residues on the α10(-) face of the α9α10 nAChR. However, mutations of these residues had little or no effect on toxin block of the α9α10 nAChR. In contrast, mutations of homologous residues in the opposing nAChR subunits (α10 Ε197, P200 and α9 T61, D121) resulted in 19- to 1700-fold loss of toxin activity. Based on the crystal structur...Continue Reading

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Citations

Jul 15, 2015·Proceedings of the National Academy of Sciences of the United States of America·Sulan LuoJ Michael McIntosh
Sep 7, 2017·Proceedings of the National Academy of Sciences of the United States of America·Abba E LefflerMandë Holford
Jan 11, 2017·Molecular Pharmacology·Juan Carlos BoffiAna Belén Elgoyhen
Aug 9, 2017·Frontiers in Cellular Neuroscience·Sean B ChristensenJ Michael McIntosh
Feb 23, 2017·Proceedings of the National Academy of Sciences of the United States of America·Haylie K RomeroJ Michael McIntosh
Jul 26, 2018·Frontiers in Pharmacology·Jhon J LópezAngélica Fierro
Dec 28, 2019·Marine Drugs·Peter N HuynhJ Michael McIntosh
May 20, 2018·Journal of Proteomics·Helena Safavi-HemamiBaldomero M Olivera
Jan 29, 2021·British Journal of Pharmacology·Teresa Minguez-ViñasAna Sofia Oliveira
Jan 28, 2020·Journal of Medicinal Chemistry·Pan XuSulan Luo

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