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Molecular Pharmacology

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Research ArticleArticle

Role in the Selectivity of Neonicotinoids of Insect-Specific Basic Residues in Loop D of the Nicotinic Acetylcholine Receptor Agonist Binding Site

Masaru Shimomura, Maiko Yokota, Makoto Ihara, Miki Akamatsu, David B. Sattelle and Kazuhiko Matsuda
Molecular Pharmacology October 2006, 70 (4) 1255-1263; DOI: https://doi.org/10.1124/mol.106.026815
Masaru Shimomura
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Maiko Yokota
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Makoto Ihara
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Miki Akamatsu
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David B. Sattelle
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Kazuhiko Matsuda
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Abstract

The insecticide imidacloprid and structurally related neonicotinoids act selectively on insect nicotinic acetylcholine receptors (nAChRs). To investigate the mechanism of neonicotinoid selectivity, we have examined the effects of mutations to basic amino acid residues in loop D of the nAChR acetylcholine (ACh) binding site on the interactions with imidacloprid. The receptors investigated are the recombinant chicken α4β2 nAChR and Drosophila melanogaster Dα2/chicken β2 hybrid nAChR expressed in Xenopus laevis oocytes. Although mutations of Thr77 in loop D of the β2 subunit resulted in a barely detectable effect on the imidacloprid concentration-response curve for the α4β2 nAChR, T77R;E79V double mutations shifted the curve dramatically to higher affinity binding of imidacloprid. Likewise, T77K;E79R and T77N;E79R double mutations in the Dα2β2 nAChR also resulted in a shift to a higher affinity for imidacloprid, which exceeded that observed for a single mutation of Thr77 to basic residues. By contrast, these double mutations scarcely influenced the ACh concentration-response curve, suggesting selective interactions with imidacloprid of the newly introduced basic residues. Computational, homology models of the agonist binding domain of the wild-type and mutant α4β2 and Dα2β2 nAChRs with imidacloprid bound were generated based on the crystal structures of acetylcholine binding proteins of Lymnaea stagnalis and Aplysia californica. The models indicate that the nitro group of imidacloprid interacts directly with the introduced basic residues at position 77, whereas those at position 79 either prevent or permit such interactions depending on their electrostatic properties, thereby explaining the observed functional changes resulting from site-directed mutagenesis.

Footnotes

  • M.S. and K.M. were supported by the Program for Promotion for Basic Research Activities for Innovative Biosciences (Bio-oriented Technology Research Advancement Institution, BRAIN). D.B.S. was supported by the Medical Research Council of the UK.

  • ABBREVIATIONS: ACh, acetylcholine; nAChR, nicotinic acetylcholine receptor; PCR, polymerase chain reaction; SOS, standard oocyte saline; PDFAMS, Protein Discovery Full Automatic Modeling System; AChBP, acetylcholine binding protein; PDB, Protein Data Bank.

    • Received May 18, 2006.
    • Accepted July 25, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 70 (4)
Molecular Pharmacology
Vol. 70, Issue 4
1 Oct 2006
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Research ArticleArticle

Role in the Selectivity of Neonicotinoids of Insect-Specific Basic Residues in Loop D of the Nicotinic Acetylcholine Receptor Agonist Binding Site

Masaru Shimomura, Maiko Yokota, Makoto Ihara, Miki Akamatsu, David B. Sattelle and Kazuhiko Matsuda
Molecular Pharmacology October 1, 2006, 70 (4) 1255-1263; DOI: https://doi.org/10.1124/mol.106.026815

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Research ArticleArticle

Role in the Selectivity of Neonicotinoids of Insect-Specific Basic Residues in Loop D of the Nicotinic Acetylcholine Receptor Agonist Binding Site

Masaru Shimomura, Maiko Yokota, Makoto Ihara, Miki Akamatsu, David B. Sattelle and Kazuhiko Matsuda
Molecular Pharmacology October 1, 2006, 70 (4) 1255-1263; DOI: https://doi.org/10.1124/mol.106.026815
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