QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: mol.107.042820v1 74/5/1407    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bertrand, D. Articles by Gopalakrishnan, M. Search for Related Content PubMed PubMed Citation Articles by Bertrand, D. Articles by Gopalakrishnan, M.

Positive Allosteric Modulation of the 7 Nicotinic Acetylcholine Receptor: Ligand Interactions with Distinct Binding Sites and Evidence for a Prominent Role of the M2-M3 Segment

Department of Neuroscience, Centre Médical Universitaire, Geneva, Switzerland (D.B., S.B.); and Neuroscience Research, Global Pharmaceutical Research & Development, Abbott Laboratories, Abbott Park, Illinois (S.C., E.G., J.L., M.G.)

The 7 nicotinic acetylcholine receptor (nAChR), a homopentameric, rapidly activating and desensitizing ligand-gated ion channel with relatively high degree of calcium permeability, is expressed in the mammalian central nervous system, including regions associated with cognitive processing. Selective agonists targeting the 7 nAChR have shown efficacy in animal models of cognitive dysfunction. Use of positive allosteric modulators selective for the 7 receptor is another strategy that is envisaged in the design of active compounds aiming at improving attention and cognitive dysfunction. The recent discovery of novel positive allosteric modulators such as 1-(5-chloro-2-hydroxyphenyl)-3-(2-chloro-5-trifluoromethylphenyl)urea (NS-1738) and 1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea (PNU-120596) that are selective for the 7 nAChRs but display significant phenotypic differences in their profile of allosteric modulation, suggests that these molecules may act at different sites on the receptor. Taking advantage of the possibility to obtain functional receptors by the fusion of proteins domains from the 7 and the 5-HT₃ receptor, we examined the structural determinants required for positive allosteric modulation. This strategy revealed that the extracellular N-terminal domain of 7 plays a critical role in allosteric modulation by NS-1738. In addition, 7-5HT₃ chimeras harboring the M2-M3 segment showed that spontaneous activity in response to NS-1738, which confirmed the critical contribution of this small extracellular segment in the receptor gating. In contrast to NS-1738, positive allosteric modulation by PNU-120596 could not be restored in the 7-5HT₃ chimeras but was selectively observed in the reverse 5HT₃-7 chimera. All together, these data illustrate the existence of distinct allosteric binding sites with specificity of different profiles of allosteric modulators and open new possibilities to investigate the 7 receptor function.

Received for publication October 19, 2007.

Accepted for publication August 1, 2008.

Address correspondence to: D. Bertrand, Dept of Neuroscience, CMU, 1, rue Michel Servet, CH-1211 Geneva 4, Switzerland. E-mail: daniel.bertrand{at}medecine.unige.ch

This article has been cited by other articles:

				G. Y. Lopez-Hernandez, J. S. Thinschmidt, G. Zheng, Z. Zhang, P. A. Crooks, L. P. Dwoskin, and R. L. Papke Selective Inhibition of Acetylcholine-Evoked Responses of {alpha}7 Neuronal Nicotinic Acetylcholine Receptors by Novel tris- and tetrakis-Azaaromatic Quaternary Ammonium Antagonists Mol. Pharmacol., September 1, 2009; 76(3): 652 - 666. [Abstract] [Full Text] [PDF]

				S. C. Barron, J. T. McLaughlin, J. A. See, V. L. Richards, and R. L. Rosenberg An Allosteric Modulator of {alpha}7 Nicotinic Receptors, N-(5-Chloro-2,4-dimethoxyphenyl)-N'-(5-methyl-3-isoxazolyl)-urea (PNU-120596), Causes Conformational Changes in the Extracellular Ligand Binding Domain Similar to Those Caused by Acetylcholine Mol. Pharmacol., August 1, 2009; 76(2): 253 - 263. [Abstract] [Full Text] [PDF]

				J. Malysz, J. H. Gronlien, D. J. Anderson, M. Hakerud, K. Thorin-Hagene, H. Ween, C. Wetterstrand, C. A. Briggs, R. Faghih, W. H. Bunnelle, et al. In Vitro Pharmacological Characterization of a Novel Allosteric Modulator of {alpha}7 Neuronal Acetylcholine Receptor, 4-(5-(4-Chlorophenyl)-2-methyl-3-propionyl-1H-pyrrol-1-yl)benzenesulfonamide (A-867744), Exhibiting Unique Pharmacological Profile J. Pharmacol. Exp. Ther., July 1, 2009; 330(1): 257 - 267. [Abstract] [Full Text] [PDF]

				A. N. de Oliveira-Pierce, R. Zhang, and T. K. Machu Colchicine: A Novel Positive Allosteric Modulator of the Human 5-Hydroxytryptamine3A Receptor J. Pharmacol. Exp. Ther., May 1, 2009; 329(2): 838 - 847. [Abstract] [Full Text] [PDF]

				R. L. Papke, W. R. Kem, F. Soti, G. Y. Lopez-Hernandez, and N. A. Horenstein Activation and Desensitization of Nicotinic {alpha}7-type Acetylcholine Receptors by Benzylidene Anabaseines and Nicotine J. Pharmacol. Exp. Ther., May 1, 2009; 329(2): 791 - 807. [Abstract] [Full Text] [PDF]