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Research ArticleArticle

Mutations at Lipid-Exposed Residues of the Acetylcholine Receptor Affect Its Gating Kinetics

Cecilia Bouzat, Ana M. Roccamo, Ingrid Garbus and F. J. Barrantes
Molecular Pharmacology July 1998, 54 (1) 146-153; DOI: https://doi.org/10.1124/mol.54.1.146
Cecilia Bouzat
Instituto de Investigaciones Bioquı́micas de Bahı́a Blanca, Universidad Nacional del Sur-Consejo Nacional de Investigaciones Cientı́ficas y Técnicas, 8000 Bahı́a Blanca, Argentina
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Ana M. Roccamo
Instituto de Investigaciones Bioquı́micas de Bahı́a Blanca, Universidad Nacional del Sur-Consejo Nacional de Investigaciones Cientı́ficas y Técnicas, 8000 Bahı́a Blanca, Argentina
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Ingrid Garbus
Instituto de Investigaciones Bioquı́micas de Bahı́a Blanca, Universidad Nacional del Sur-Consejo Nacional de Investigaciones Cientı́ficas y Técnicas, 8000 Bahı́a Blanca, Argentina
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F. J. Barrantes
Instituto de Investigaciones Bioquı́micas de Bahı́a Blanca, Universidad Nacional del Sur-Consejo Nacional de Investigaciones Cientı́ficas y Técnicas, 8000 Bahı́a Blanca, Argentina
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Abstract

The firmest candidate among the transmembrane portions of the nicotinic acetylcholine receptor (AChR) to be in contact with the lipid bilayer is the fourth segment, M4. To explore the contribution of αM4 amino acid residues of mouse AChR to channel gating, we combined site-directed mutagenesis with single-channel recordings. Two residues in αM4, Cys418 and Thr422, were found to significantly affect gating kinetics when replaced by alanine. AChRs containing αC418A and αT422A subunits form channels characterized by a 3- and 5-fold reduction in the mean open time, respectively, suggesting an increase in the closing rate due to the mutations. The calculated changes in the energy barrier for the channel closing process show unequal and coupled contributions of both positions to channel gating. Single-channel recordings of hybrid wild-type α/αT422A AChR show that the closing rate depends on the number of α subunits mutated. Each substitution of threonine to alanine changes the energy barrier of the closing process by ∼0.5 kcal/mol. Recordings of channels activated by high agonist concentration suggest that these mutations also impair channel opening. Both Cys418 and Thr422 have been postulated to be in contact with the lipid milieu and are highly conserved among species and subunits. Our results support the involvement of lipid-exposed residues in αM4 in AChR channel gating mechanism.

Footnotes

    • Received December 29, 1997.
    • Accepted March 20, 1998.
  • Send reprint requests to: Dr. Cecilia Bouzat, Instituto de Investigaciones Bioquı́micas, CC 857-Camino La Carrindanga Km 7, 8000 Bahı́a Blanca, Argentina. E-mail:inbouzat{at}criba.edu.ar

  • This work was supported by grants from the Universidad Nacional del Sur, Argentinian Scientific Research Council (Consejo Nacional de Investigaciones Cientı́ficas y Técnicas), Scientific Research Commission of the Province of Buenos Aires (Comisión de Investigación Científica de la Provincia de Buenos Aires), and European Union (Grant CI1*-CT94–0127 to F.J.B.).

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 54 (1)
Molecular Pharmacology
Vol. 54, Issue 1
1 Jul 1998
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Research ArticleArticle

Mutations at Lipid-Exposed Residues of the Acetylcholine Receptor Affect Its Gating Kinetics

Cecilia Bouzat, Ana M. Roccamo, Ingrid Garbus and F. J. Barrantes
Molecular Pharmacology July 1, 1998, 54 (1) 146-153; DOI: https://doi.org/10.1124/mol.54.1.146

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Research ArticleArticle

Mutations at Lipid-Exposed Residues of the Acetylcholine Receptor Affect Its Gating Kinetics

Cecilia Bouzat, Ana M. Roccamo, Ingrid Garbus and F. J. Barrantes
Molecular Pharmacology July 1, 1998, 54 (1) 146-153; DOI: https://doi.org/10.1124/mol.54.1.146
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