Boffi, J.C.; Marcovich, I.; Gill-Thind, J.K.; Corradi, J.; Collins, T.; Lipovsek, M.M.; Moglie, M.; Plazas, P.V.; Craig, P.O.; Millar, N.S.; Bouzat, C.; Elgoyhen, A.B."Differential contribution of subunit interfaces to α9α10 nicotinic acetylcholine receptor function" (2017) Molecular Pharmacology. 91(3):250-262
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Nicotinic acetylcholine receptors can be assembled from either homomeric or heteromeric pentameric subunit combinations. At the interface of the extracellular domains of adjacent subunits lies the acetylcholine binding site, composed of a principal component provided by one subunit and a complementary component of the adjacent subunit. Compared with neuronal nicotinic acetylcholine cholinergic receptors (nAChRs) assembled from α and β subunits, the α9α10 receptor is an atypical member of the family. It is a heteromeric receptor composed only of α subunits. Whereas mammalian α9 subunits can form functional homomeric α9 receptors, α10 subunits do not generate functional channels when expressed heterologously. Hence, it has been proposed that α10 might serve as a structural subunit, much like a β subunit of heteromeric nAChRs, providing only complementary components to the agonist binding site. Here, we have made use of site-directed mutagenesis to examine the contribution of subunit interface domains to α9α10 receptors by a combination of electrophysiological and radioligand binding studies. Characterization of receptors containing Y190T mutations revealed unexpectedly that both α9 and α10 subunits equally contribute to the principal components of the α9α10 nAChR. In addition, we have shown that the introduction of a W55T mutation impairs receptor binding and function in the rat α9 subunit but not in the α10 subunit, indicating that the contribution of α9 and α10 subunits to complementary components of the ligand-binding site is non-equivalent. We conclude that this asymmetry, which is supported by molecular docking studies, results from adaptive amino acid changes acquired only during the evolution of mammalian α10 subunits. Copyright © 2017 by The Author(s).


Documento: Artículo
Título:Differential contribution of subunit interfaces to α9α10 nicotinic acetylcholine receptor function
Autor:Boffi, J.C.; Marcovich, I.; Gill-Thind, J.K.; Corradi, J.; Collins, T.; Lipovsek, M.M.; Moglie, M.; Plazas, P.V.; Craig, P.O.; Millar, N.S.; Bouzat, C.; 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
Instituto de Química Biológica, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
Instituto de Investigaciones Bioquímicas de Bahía Blanca, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
Department of Neuroscience, Physiology and Pharmacology, University College London, United Kingdom
Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
Instituto de Farmacología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur, Bahía Blanca, Argentina
Department of Functional Neuroanatomy, Institute for Anatomy and Cell Biology, University of Heidelberg, Heidelberg, Germany
Centre for Developmental Neurobiology, King's College, London, United Kingdom
Palabras clave:nicotinic receptor; receptor subunit; acetylcholine; nicotinic receptor; protein subunit; animal cell; Article; binding site; controlled study; molecular docking; molecular model; nonhuman; priority journal; protein domain; rat; receptor binding; site directed mutagenesis; amino acid sequence; animal; chemistry; chicken; genetics; metabolism; mutation; protein secondary structure; protein subunit; structural homology; structure activity relation; Acetylcholine; Amino Acid Sequence; Animals; Binding Sites; Chickens; Molecular Docking Simulation; Mutation; Protein Structure, Secondary; Protein Subunits; Rats; Receptors, Nicotinic; Structural Homology, Protein; Structure-Activity Relationship
Página de inicio:250
Página de fin:262
Título revista:Molecular Pharmacology
Título revista abreviado:Mol. Pharmacol.
CAS:acetylcholine, 51-84-3, 60-31-1, 66-23-9; Acetylcholine; Protein Subunits; Receptors, Nicotinic


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---------- APA ----------
Boffi, J.C., Marcovich, I., Gill-Thind, J.K., Corradi, J., Collins, T., Lipovsek, M.M., Moglie, M.,..., Elgoyhen, A.B. (2017) . Differential contribution of subunit interfaces to α9α10 nicotinic acetylcholine receptor function. Molecular Pharmacology, 91(3), 250-262.
---------- CHICAGO ----------
Boffi, J.C., Marcovich, I., Gill-Thind, J.K., Corradi, J., Collins, T., Lipovsek, M.M., et al. "Differential contribution of subunit interfaces to α9α10 nicotinic acetylcholine receptor function" . Molecular Pharmacology 91, no. 3 (2017) : 250-262.
---------- MLA ----------
Boffi, J.C., Marcovich, I., Gill-Thind, J.K., Corradi, J., Collins, T., Lipovsek, M.M., et al. "Differential contribution of subunit interfaces to α9α10 nicotinic acetylcholine receptor function" . Molecular Pharmacology, vol. 91, no. 3, 2017, pp. 250-262.
---------- VANCOUVER ----------
Boffi, J.C., Marcovich, I., Gill-Thind, J.K., Corradi, J., Collins, T., Lipovsek, M.M., et al. Differential contribution of subunit interfaces to α9α10 nicotinic acetylcholine receptor function. Mol. Pharmacol. 2017;91(3):250-262.