J Pharmacol Exp Ther 2009 Jul 01;3301:40-53. doi: 10.1124/jpet.109.151225.

Differential regulation of receptor activation and agonist selectivity by highly conserved tryptophans in the nicotinic acetylcholine receptor binding site.

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We have shown previously that a highly conserved Tyr in the nicotinic acetylcholine receptor (nAChR) ligand-binding domain (LBD) (alpha7 Tyr188 or alpha4 Tyr195) differentially regulates the activity of acetylcholine (ACh) and the alpha7-selective agonist 3-(4-hydroxy,2-methoxybenzylidene)anabaseine (4OH-GTS-21) in alpha4beta2 and alpha7 nAChR. In this study, we mutated two highly conserved LBD Trp residues in human alpha7 and alpha4beta2 and expressed the receptors in Xenopus laevis oocytes. Alpha7 receptors with Trp55 mutated to Gly or Tyr became less responsive to 4OH-GTS-21, whereas mutation of the homologous Trp57 in beta2 to Gly, Tyr, Phe, or Ala resulted in alpha4beta2 receptors that showed increased responses to 4OH-GTS-21. Mutation of alpha7 Trp55 to Val resulted in receptors for which the partial agonist 4OH-GTS-21 became equally efficacious as ACh, whereas alpha4beta2 receptors with the homologous mutation remained nonresponsive to 4OH-GTS-21. In contrast to the striking alterations in agonist activity profiles that were observed with mutations of alpha7 Trp55 and beta2 Trp57, mutations of alpha7 Trp149 or alpha4 Trp154 universally resulted in receptors with reduced function. Our data support the hypothesis that some conserved residues in the nAChR LBD differentially regulate receptor activation by subtype-selective agonists, whereas other equally well conserved residues play fundamental roles in receptor activation by any agonist. Residues like alpha7 Trp149 (alpha4 Trp154) may be considered pillars upon which basic receptor function depends, whereas alpha7 Trp55 (beta2 Trp57) and alpha7 Tyr188 (alpha4 Tyr195) may be fulcra upon which agonists may operate differentially in specific receptor subtypes, consistent with the hypothesis that ACh and 4OH-GTS-21 are able to activate nAChR in distinct ways.

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