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Tracking the molecular evolution of calcium permeability in a nicotinic acetylcholine receptor.
Lipovsek, Marcela; Fierro, Angélica; Pérez, Edwin G; Boffi, Juan C; Millar, Neil S; Fuchs, Paul A; Katz, Eleonora; Elgoyhen, Ana Belén.
Afiliação
  • Lipovsek M; Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, Dr. Héctor N Torres, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina marcela.lipovsek@gmail.com.
  • Fierro A; Department of Organic Chemistry, Faculty of Chemistry, Pontificia Universidad Católica de Chile, Santiago, Chile.
  • Pérez EG; Department of Organic Chemistry, Faculty of Chemistry, Pontificia Universidad Católica de Chile, Santiago, Chile.
  • Boffi JC; Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, Dr. Héctor N Torres, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina.
  • Millar NS; Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom.
  • Fuchs PA; Department of Otolaryngology, Head and Neck Surgery, and Center for Hearing and Balance, The Johns Hopkins University School of Medicine, Baltimore, MD.
  • Katz E; Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, Dr. Héctor N Torres, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos
  • Elgoyhen AB; Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, Dr. Héctor N Torres, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina Departamento de Farmacología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.
Mol Biol Evol ; 31(12): 3250-65, 2014 Dec.
Article em En | MEDLINE | ID: mdl-25193338
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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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Cálcio / Receptores Nicotínicos Limite: Animals / Humans Idioma: En Revista: Mol Biol Evol Assunto da revista: BIOLOGIA MOLECULAR Ano de publicação: 2014 Tipo de documento: Article País de afiliação: Argentina País de publicação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Cálcio / Receptores Nicotínicos Limite: Animals / Humans Idioma: En Revista: Mol Biol Evol Assunto da revista: BIOLOGIA MOLECULAR Ano de publicação: 2014 Tipo de documento: Article País de afiliação: Argentina País de publicação: Estados Unidos