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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 42 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

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Copyright © 1998 Society for Neuroscience  0270-6474/98/182648-10$05.00/0

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