Artículo

Lipovsek, M.; Fierro, A.; Pérez, E.G.; Boffi, J.C.; Millar, N.S.; Fuchs, P.A.; Katz, E.; Elgoyhen, A.B. "Tracking the molecular evolution of calcium permeability in a nicotinic acetylcholine receptor" (2014) Molecular Biology and Evolution. 31(12):3250-3265
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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 α 9α 10 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 α 9α 10 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 α 9α 10 mammalian receptor. Only three specific amino acid substitutions in the α 9 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. © The Author 2014. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Registro:

Documento: Artículo
Título:Tracking the molecular evolution of calcium permeability in a nicotinic acetylcholine receptor
Autor:Lipovsek, M.; Fierro, A.; Pérez, E.G.; Boffi, J.C.; Millar, N.S.; Fuchs, P.A.; Katz, E.; Elgoyhen, A.B.
Filiación:Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, Dr. Héctor N Torres, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
Department of Organic Chemistry, Faculty of Chemistry, Pontificia Universidad Católica de Chile, Santiago, Chile
Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom
Department of Otolaryngology, Head and Neck Surgery, Center for Hearing and Balance, Johns Hopkins University School of Medicine, Baltimore, MD, United States
Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
Departamento de Farmacología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
MRC Centre for Developmental Neurobiology, King's College London, London, United Kingdom
Palabras clave:calcium permeability; hearing; molecular evolution; nicotinic receptors; calcium; nicotinic receptor; acetylcholine; avian protein; calcium; nicotinic agent; nicotinic receptor; amino acid sequence; amino acid substitution; animal cell; Article; calcium transport; cell membrane; chicken; evoked response; extracellular calcium; female; mammal; molecular dynamics; molecular evolution; mutagenesis; mutant; nonhuman; oocyte; permeability; phylogeny; protein structure; rat; vestibule; voltage clamp technique; Xenopus laevis; animal; calcium signaling; cell culture; chemistry; genetics; human; metabolism; molecular evolution; molecular genetics; permeability; Aves; Mammalia; Acetylcholine; Amino Acid Sequence; Animals; Avian Proteins; Calcium; Calcium Signaling; Cell Membrane; Cells, Cultured; Chickens; Evolution, Molecular; Humans; Molecular Dynamics Simulation; Molecular Sequence Data; Nicotinic Agonists; Permeability; Rats; Receptors, Nicotinic; Xenopus laevis
Año:2014
Volumen:31
Número:12
Página de inicio:3250
Página de fin:3265
DOI: http://dx.doi.org/10.1093/molbev/msu258
Título revista:Molecular Biology and Evolution
Título revista abreviado:Mol. Biol. Evol.
ISSN:07374038
CODEN:MBEVE
CAS:calcium, 7440-70-2, 14092-94-5; acetylcholine, 51-84-3, 60-31-1, 66-23-9; Acetylcholine; Avian Proteins; Calcium; Nicotinic Agonists; Receptors, Nicotinic
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_07374038_v31_n12_p3250_Lipovsek

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Citas:

---------- APA ----------
Lipovsek, M., Fierro, A., Pérez, E.G., Boffi, J.C., Millar, N.S., Fuchs, P.A., Katz, E.,..., Elgoyhen, A.B. (2014) . Tracking the molecular evolution of calcium permeability in a nicotinic acetylcholine receptor. Molecular Biology and Evolution, 31(12), 3250-3265.
http://dx.doi.org/10.1093/molbev/msu258
---------- CHICAGO ----------
Lipovsek, M., Fierro, A., Pérez, E.G., Boffi, J.C., Millar, N.S., Fuchs, P.A., et al. "Tracking the molecular evolution of calcium permeability in a nicotinic acetylcholine receptor" . Molecular Biology and Evolution 31, no. 12 (2014) : 3250-3265.
http://dx.doi.org/10.1093/molbev/msu258
---------- MLA ----------
Lipovsek, M., Fierro, A., Pérez, E.G., Boffi, J.C., Millar, N.S., Fuchs, P.A., et al. "Tracking the molecular evolution of calcium permeability in a nicotinic acetylcholine receptor" . Molecular Biology and Evolution, vol. 31, no. 12, 2014, pp. 3250-3265.
http://dx.doi.org/10.1093/molbev/msu258
---------- VANCOUVER ----------
Lipovsek, M., Fierro, A., Pérez, E.G., Boffi, J.C., Millar, N.S., Fuchs, P.A., et al. Tracking the molecular evolution of calcium permeability in a nicotinic acetylcholine receptor. Mol. Biol. Evol. 2014;31(12):3250-3265.
http://dx.doi.org/10.1093/molbev/msu258