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Molecular Pharmacology

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Research ArticleArticle

Mutations of a Conserved Lysine Residue in the N-Terminal Domain of α7 Nicotinic Receptors Affect Gating and Binding of Nicotinic Agonists

Manuel Criado, José Mulet, José A. Bernal, Susana Gerber, Salvador Sala and Francisco Sala
Molecular Pharmacology December 2005, 68 (6) 1669-1677; DOI: https://doi.org/10.1124/mol.105.015446
Manuel Criado
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José Mulet
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José A. Bernal
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Susana Gerber
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Salvador Sala
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Francisco Sala
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Abstract

Activation of nicotinic acetylcholine receptors is initiated by binding of agonists, and as a consequence, specific domains transmit the chemical signal to the channel gate through a sequence of conformational changes. Recent high-resolution structural data from a snail acetylcholine binding protein have shown that the side chain of a lysine residue, located in the β-strand β7 and strictly conserved in α subunits of nicotinic receptors, systematically moves upon agonist binding, suggesting that it might be involved in both binding and gating. To test this hypothesis in neuronal nicotinic receptors, Lys145 was substituted by other amino acids in the α7 nicotinic receptor, and expression levels and electrophysiological responses for several nicotinic agonists and antagonists were determined. Substitutions of Lys145 showed a variety of functional effects: 1) strong reductions in the functional responses to acetylcholine, nicotine, and dimethylphenylpiperazinium, the latter becoming an antagonist; 2) increases in the agonist EC50 values (up to 80-fold with acetylcholine); 3) heterogeneous behavior of the different agonists, with epibatidine and cytisine being less affected by the substitutions; 4) decreases of agonist affinities for the desensitized receptors; and 5) small changes in the affinity of nicotinic antagonists. It is concluded that the presence of a polar or positively charged side chain at this position improves the gating function with acetylcholine and nicotine, although the lysine side chain seems to be necessary for retaining the binding properties of acetylcholine. The results are compatible with the involvement of Lys145 in the early steps of channel activation by acetylcholine.

  • Received June 1, 2005.
  • Accepted August 29, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 68 (6)
Molecular Pharmacology
Vol. 68, Issue 6
1 Dec 2005
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Research ArticleArticle

Mutations of a Conserved Lysine Residue in the N-Terminal Domain of α7 Nicotinic Receptors Affect Gating and Binding of Nicotinic Agonists

Manuel Criado, José Mulet, José A. Bernal, Susana Gerber, Salvador Sala and Francisco Sala
Molecular Pharmacology December 1, 2005, 68 (6) 1669-1677; DOI: https://doi.org/10.1124/mol.105.015446

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Research ArticleArticle

Mutations of a Conserved Lysine Residue in the N-Terminal Domain of α7 Nicotinic Receptors Affect Gating and Binding of Nicotinic Agonists

Manuel Criado, José Mulet, José A. Bernal, Susana Gerber, Salvador Sala and Francisco Sala
Molecular Pharmacology December 1, 2005, 68 (6) 1669-1677; DOI: https://doi.org/10.1124/mol.105.015446
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