Combined roles of loops C and D in the interactions of a neonicotinoid insecticide imidacloprid with the α4β2 nicotinic acetylcholine receptor

Kayoko Toshima, Satoshi Kanaoka, Atsushi Yamada, Kiyoshi Tarumoto, Miki Akamatsu, David B. Sattelle, Kazuhiko Matsuda

    Research output: Contribution to journalArticlepeer-review

    Abstract

    Neonicotinoid insecticides are widely used for crop protection based on their selective actions on insect nicotinic acetylcholine receptors (insect nAChRs). Loops C and D in insect nAChRs have been shown to possess structural features favorable for neonicotinoid-nAChR interactions. However, it remains to be resolved whether such features serve either co-operatively, or independently, to enhance neonicotinoid sensitivity of nAChRs. We therefore examined using voltage-clamp electrophysiology the effects on the response to imidacloprid of combinatorial substitutions of residues in loops C and D of the chicken α4β2 nAChR by those present in insect nAChRs. The E219P mutation in loop C of the α4 subunit resulted in enhanced responses to imidacloprid of α4β2, whereas E219S and E219T mutations barely influenced its actions. On the other hand, mutations in loop D (T77R; E79V and T77N; E79R) alone shifted the imidacloprid concentration-response curve to the left (lower concentrations). Interestingly, all three mutations did, however, further enhance the agonist efficacy of imidacloprid when combined with the mutations in loop D. Such synergistic effects of the two loops on the interactions with imidaclprid were observed irrespective of subunit stoichiometry. Computational modeling of the ligand binding domain of the wild-type and mutant α4β2 nAChRs using the crystal structure of the acetylcholine binding protein from Lymnaea stagnalis also indicated that interactions with loop F of loops C and D may contribute to determining the response to imidacloprid. © 2008 Elsevier Ltd. All rights reserved.
    Original languageEnglish
    Pages (from-to)264-272
    Number of pages8
    JournalNeuropharmacology
    Volume56
    Issue number1
    DOIs
    Publication statusPublished - Jan 2009

    Keywords

    • Acetylcholine binding protein
    • Chicken α4β2 nicotinic receptor
    • Homology modeling
    • Imidacloprid
    • Ion channels
    • Ligand binding domain
    • Neonicotinoids
    • Nicotinic acetylcholine receptor

    Fingerprint

    Dive into the research topics of 'Combined roles of loops C and D in the interactions of a neonicotinoid insecticide imidacloprid with the α4β2 nicotinic acetylcholine receptor'. Together they form a unique fingerprint.

    Cite this