ArticleMolecular biology and evolution2014
Tracking the molecular evolution of calcium permeability in a nicotinic acetylcholine receptor.
Article in Molecular biology and evolution, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 47 citations in OpenAlex.
- Drug Discovery Targeting Nicotinic Acetylcholine Receptors for Hearing Loss.International journal of molecular sciences · 2026Review
- Human α10 nicotinic acetylcholine receptor subunits assemble to form functional receptors.The Journal of biological chemistry · 2025Article
- Key role of the TM2-TM3 loop in calcium potentiation of the α9α10 nicotinic acetylcholine receptor.Cellular and molecular life sciences : CMLS · 2024Article
- Explorations of Agonist Selectivity for the α9* nAChR with Novel Substituted Carbamoyl/Amido/Heteroaryl Dialkylpiperazinium Salts and Their Therapeutic Implications in Pain and Inflammation.Journal of medicinal chemistry · 2024Article
- Ion-Powered Rotary Motors: Where Did They Come from and Where They Are Going?International journal of molecular sciences · 2023Review
- The Remarkable Outer Hair Cell: Proceedings of a Symposium in Honour of W. E. Brownell.Journal of the Association for Research in Otolaryngology : JARO · 2023Review
- Alkaloid ligands enable function of homomeric human α10 nicotinic acetylcholine receptors.Frontiers in pharmacology · 2022Article
- Comparison of the Anti-inflammatory Properties of Two Nicotinic Acetylcholine Receptor Ligands, Phosphocholine andFrontiers in cellular neuroscience · 2022Article
- Positively selected genes in the hoary bat (PeerJ · 2022Article
- Unraveling the Molecular Players at the Cholinergic Efferent Synapse of the Zebrafish Lateral Line.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2021Article
- Multidimensional Intersection of Nicotine, Gene Expression, and Behavior.Frontiers in behavioral neuroscience · 2021Article
- The Hair Cell α9α10 Nicotinic Acetylcholine Receptor: Odd Cousin in an Old Family.Frontiers in cellular neuroscience · 2021Review
- The Cholinergic Lateral Line Efferent Synapse: Structural, Functional and Molecular Similarities With Those of the Cochlea.Frontiers in cellular neuroscience · 2021Review
- Loss of Choline Agonism in the Inner Ear Hair Cell Nicotinic Acetylcholine Receptor Linked to the α10 Subunit.Frontiers in molecular neuroscience · 2021Article
- Hair cell α9α10 nicotinic acetylcholine receptor functional expression regulated by ligand binding and deafness gene products.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Distinct Evolutionary Trajectories of Neuronal and Hair Cell Nicotinic Acetylcholine Receptors.Molecular biology and evolution · 2020Article
- Efferent Inhibition of the Cochlea.Cold Spring Harbor perspectives in medicine · 2019Review
- Nicotinic acetylcholine receptors regulate vestibular afferent gain and activation timing.The Journal of comparative neurology · 2017Article
- Functional roles of T3.37 and S5.46 in the activation mechanism of the dopamine D1 receptor.Journal of molecular modeling · 2017Article
- Differential Contribution of Subunit Interfaces to α9α10 Nicotinic Acetylcholine Receptor Function.Molecular pharmacology · 2017Article
Corrections and comments
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Authors and funding
8 authors at 7 institutions in 4 countries.
Funding
Abstract
Nicotinic acetylcholine receptors are a family of ligand-gated nonselective cationic channels that participate in fundamental physiological processes at both the central and the peripheral nervous system. The extent of calcium entry through ligand-gated ion channels defines their distinct functions. The α9α10 nicotinic cholinergic receptor, expressed in cochlear hair cells, is a peculiar member of the family as it shows differences in the extent of calcium permeability across species. In particular, mammalian α9α10 receptors are among the ligand-gated ion channels which exhibit the highest calcium selectivity. This acquired differential property provides the unique opportunity of studying how protein function was shaped along evolutionary history, by tracking its evolutionary record and experimentally defining the amino acid changes involved. We have applied a molecular evolution approach of ancestral sequence reconstruction, together with molecular dynamics simulations and an evolutionary-based mutagenesis strategy, in order to trace the molecular events that yielded a high calcium permeable nicotinic α9α10 mammalian receptor. Only three specific amino acid substitutions in the α9 subunit were directly involved. These are located at the extracellular vestibule and at the exit of the channel pore and not at the transmembrane region 2 of the protein as previously thought. Moreover, we show that these three critical substitutions only increase calcium permeability in the context of the mammalian but not the avian receptor, stressing the relevance of overall protein structure on defining functional properties. These results highlight the importance of tracking evolutionarily acquired changes in protein sequence underlying fundamental functional properties of ligand-gated ion channels.
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