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The Journal of Neuroscience, January 15, 1998, 18(2):648-657
Critical Elements Determining Diversity in Agonist Binding and
Desensitization of Neuronal Nicotinic Acetylcholine Receptors
Pierre-Jean
Corringer1,
Sonia
Bertrand2,
Sébastien
Bohler1,
Stuart J.
Edelstein3,
Jean-Pierre
Changeux1, and
Daniel
Bertrand2
1 Neurobiologie Moléculaire, Unité de
Recherche Associée au Centre National de la Recherche
Scientifique D1284, Institut Pasteur, 75724 Paris Cedex 15, France,
2 Département de Physiologie, Centre Médical
Universitaire (Faculté de Médecine), 1211 Geneva 4, Switzerland, and 3 Département de Biochimie,
Université de Genève, CH-1211 Geneva, Switzerland
To identify the molecular determinants underlying the
pharmacological diversity of neuronal nicotinic acetylcholine
receptors, we compared the  7 homo-oligomeric and 4 2
hetero-oligomeric receptors. Sets of residues from the regions
initially identified within the agonist binding site of the 4
subunit were introduced into the 7 agonist binding site, carried by
the homo-oligomeric 7-V201-5HT3 chimera. Introduction
of the 4 residues 183-191 into 7 subunit sequence (chimera
C2) selectively increased the apparent affinities for
equilibrium binding and for ion channel activation by acetylcholine,
resulting in a receptor that no longer displays differences in the
responses to acetylcholine and nicotine. Introduction of the 4
residues 151-155 (chimera B) produced a ~100-fold increase in the
apparent affinity for both acetylcholine and nicotine in
equilibrium binding measurements. In both cases electrophysiological
recordings revealed a much smaller increase (three- to sevenfold) in
the apparent affinity for activation, but the concentrations required
to desensitize the mutant chimeras parallel the shifts in apparent
binding affinity. The data were fitted by a two-state concerted model,
and an alteration of the conformational isomerization constant leading
to the desensitized state accounts for the chimera B phenotype, whereas
alteration of the ligand binding site accounts for the chimera
C2 phenotype. Point mutation analysis revealed that several
residues in both fragments contribute to the phenotypes, with a
critical effect of the G152K and T183N mutations. Transfer of 4
amino acids 151-155 and 183-191 into the 7-V201-5HT3
chimera thus confers physiological and pharmacological properties
typical of the 42 receptor.
Key words:
nicotinic receptor; neuronal; acetylcholine; desensitization; pharmacology; chimera
Copyright © 1998 Society for Neuroscience 0270-6474/98/182648-10$05.00/0
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