Tracking the molecular evolution of calcium permeability in a nicotinic acetylcholine receptor
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....
Guardado en:
| Autores principales: | , , , , , , , |
|---|---|
| Formato: | JOUR |
| Materias: | |
| Acceso en línea: | http://hdl.handle.net/20.500.12110/paper_07374038_v31_n12_p3250_Lipovsek |
| Aporte de: |
| id |
todo:paper_07374038_v31_n12_p3250_Lipovsek |
|---|---|
| record_format |
dspace |
| spelling |
todo:paper_07374038_v31_n12_p3250_Lipovsek2023-10-03T15:38:00Z Tracking the molecular evolution of calcium permeability in a nicotinic acetylcholine receptor Lipovsek, M. Fierro, A. Pérez, E.G. Boffi, J.C. Millar, N.S. Fuchs, P.A. Katz, E. Elgoyhen, A.B. 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 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. Fil:Lipovsek, M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Boffi, J.C. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Katz, E. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_07374038_v31_n12_p3250_Lipovsek |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
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 |
| spellingShingle |
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 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 |
| topic_facet |
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 |
| description |
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. |
| format |
JOUR |
| author |
Lipovsek, M. Fierro, A. Pérez, E.G. Boffi, J.C. Millar, N.S. Fuchs, P.A. Katz, E. Elgoyhen, A.B. |
| author_facet |
Lipovsek, M. Fierro, A. Pérez, E.G. Boffi, J.C. Millar, N.S. Fuchs, P.A. Katz, E. Elgoyhen, A.B. |
| author_sort |
Lipovsek, M. |
| title |
Tracking the molecular evolution of calcium permeability in a nicotinic acetylcholine receptor |
| title_short |
Tracking the molecular evolution of calcium permeability in a nicotinic acetylcholine receptor |
| title_full |
Tracking the molecular evolution of calcium permeability in a nicotinic acetylcholine receptor |
| title_fullStr |
Tracking the molecular evolution of calcium permeability in a nicotinic acetylcholine receptor |
| title_full_unstemmed |
Tracking the molecular evolution of calcium permeability in a nicotinic acetylcholine receptor |
| title_sort |
tracking the molecular evolution of calcium permeability in a nicotinic acetylcholine receptor |
| url |
http://hdl.handle.net/20.500.12110/paper_07374038_v31_n12_p3250_Lipovsek |
| work_keys_str_mv |
AT lipovsekm trackingthemolecularevolutionofcalciumpermeabilityinanicotinicacetylcholinereceptor AT fierroa trackingthemolecularevolutionofcalciumpermeabilityinanicotinicacetylcholinereceptor AT perezeg trackingthemolecularevolutionofcalciumpermeabilityinanicotinicacetylcholinereceptor AT boffijc trackingthemolecularevolutionofcalciumpermeabilityinanicotinicacetylcholinereceptor AT millarns trackingthemolecularevolutionofcalciumpermeabilityinanicotinicacetylcholinereceptor AT fuchspa trackingthemolecularevolutionofcalciumpermeabilityinanicotinicacetylcholinereceptor AT katze trackingthemolecularevolutionofcalciumpermeabilityinanicotinicacetylcholinereceptor AT elgoyhenab trackingthemolecularevolutionofcalciumpermeabilityinanicotinicacetylcholinereceptor |
| _version_ |
1782023834242646016 |