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

This Article Full Text Full Text (PDF) 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 Stokes, C. Articles by Papke, R. L. Search for Related Content PubMed PubMed Citation Articles by Stokes, C. Articles by Papke, R. L.

The Structural Basis for GTS-21 Selectivity between Human and Rat Nicotinic 7 Receptors

Department of Pharmacology and Therapeutics, University of Florida College of Medicine, Gainesville, Florida (C.S., J.K.P.P., W.R.K., T.J.M., R.L.P.); and Department of Chemistry, University of Florida, Gainesville, Florida (N.A.H.)

The 7 nAChR-selective partial agonist 3-(2,4-dimethoxybenzylidene)anabaseine (GTS-21) is more efficacious and potent for rat receptors than for human 7 receptors. Four single amino acid differences exist between human and rat 7 in the agonist binding site, two in the C loop, and one each in the E and F loops. Reciprocal mutations were made in these three domains and evaluated in Xenopus laevis oocytes. Mutations in the C and F loops significantly increased the efficacy of GTS-21 for the human receptor mutants but not to the level of the wild-type, and reciprocal mutations in rat 7 did not decrease responses to GTS-21. Whereas mutations in the E loop alone were without effect, the E- and F-loop mutations together increased GTS-21 efficacy and potency for human receptors, but the EF mutations in the rat receptors decreased the GTS-21 potency without changing the efficacy. The only mutants that showed a full reversal of the efficacy differences between human and rat 7 contained complete exchange of all four sites in the C, E, and F loops or just the sites in the C and F loops. However, the reversal of the potency ratio seen with the EF mutants was not evident in the CEF mutants. Our data therefore indicate that the pharmacological differences between rat and human 7 receptors are caused by reciprocal differences in sites within and around the binding site. Specific features in the agonist molecule itself are also identified that interact with these structural features of the receptor agonist binding site.

Address correspondence to: Dr. Roger L. Papke, Department of Pharmacology and Therapeutics, P.O. Box 100267, 1600 SW Archer Rd., University of Florida, College of Medicine, Gainesville, FL 32610. E-mail: rlpapke{at}ufl.edu

This article has been cited by other articles:

				F. Levitin, M. Weiss, Y. Hahn, O. Stern, R. L. Papke, R. Matusik, S. R. Nandana, R. Ziv, E. Pichinuk, S. Salame, et al. PATE Gene Clusters Code for Multiple, Secreted TFP/Ly-6/uPAR Proteins That Are Expressed in Reproductive and Neuron-rich Tissues and Possess Neuromodulatory Activity J. Biol. Chem., June 13, 2008; 283(24): 16928 - 16939. [Abstract] [Full Text] [PDF]

				R. W. Buchanan, R. Freedman, D. C. Javitt, A. Abi-Dargham, and J. A. Lieberman Recent Advances in the Development of Novel Pharmacological Agents for the Treatment of Cognitive Impairments in Schizophrenia Schizophr Bull, September 1, 2007; 33(5): 1120 - 1130. [Abstract] [Full Text] [PDF]

				F. G. Boess, J. De Vry, C. Erb, T. Flessner, M. Hendrix, J. Luithle, C. Methfessel, B. Riedl, K. Schnizler, F.-J. van der Staay, et al. The Novel {alpha}7 Nicotinic Acetylcholine Receptor Agonist N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-7-[2-(methoxy)phenyl]-1-benzofuran-2-carboxamide Improves Working and Recognition Memory in Rodents J. Pharmacol. Exp. Ther., May 1, 2007; 321(2): 716 - 725. [Abstract] [Full Text] [PDF]

				N. A. Horenstein, T. J. McCormack, C. Stokes, K. Ren, and R. L. Papke Reversal of Agonist Selectivity by Mutations of Conserved Amino Acids in the Binding Site of Nicotinic Acetylcholine Receptors J. Biol. Chem., February 23, 2007; 282(8): 5899 - 5909. [Abstract] [Full Text] [PDF]

				A. Olincy, J. G. Harris, L. L. Johnson, V. Pender, S. Kongs, D. Allensworth, J. Ellis, G. O. Zerbe, S. Leonard, K. E. Stevens, et al. Proof-of-Concept Trial of an {alpha}7 Nicotinic Agonist in Schizophrenia. Arch Gen Psychiatry, June 1, 2006; 63(6): 630 - 638. [Abstract] [Full Text] [PDF]

				R. Zhang, N. A. White, F. S. Soti, W. R. Kem, and T. K. Machu N-Terminal Domains in Mouse and Human 5-Hydroxytryptamine3A Receptors Confer Partial Agonist and Antagonist Properties to Benzylidene Analogs of Anabaseine J. Pharmacol. Exp. Ther., June 1, 2006; 317(3): 1276 - 1284. [Abstract] [Full Text] [PDF]