Role of loop D of the α7 nicotinic acetylcholine receptor in its interaction with the insecticide imidacloprid and related neonicotinoids
Article first published online: 29 JAN 2009
2000 British Pharmacological Society
British Journal of Pharmacology
Volume 130, Issue 5, pages 981–986, July 2000
How to Cite
Matsuda, K., Shimomura, M., Kondo, Y., Ihara, M., Hashigami, K., Yoshida, N., Raymond, V., Mongan, N. P., Freeman, J. C., Komai, K. and Sattelle, D. B. (2000), Role of loop D of the α7 nicotinic acetylcholine receptor in its interaction with the insecticide imidacloprid and related neonicotinoids. British Journal of Pharmacology, 130: 981–986. doi: 10.1038/sj.bjp.0703374
- Issue published online: 29 JAN 2009
- Article first published online: 29 JAN 2009
- (Received February 2, 2000, Revised March 8, 2000, Accepted March 20, 2000)
- Nicotinic acetylcholine receptor;
- α7 subunit;
- negative subsite mutations;
The nitroguanidine insecticide imidacloprid along with a second generation of related compounds including nitenpyram, all nicotinic acetylcholine (ACh) receptor ligands, are used increasingly in many countries. Site-directed mutagenesis and heterologous expression in Xenopus laevis oocytes have been deployed to investigate mutants (G189D and G189E) of the chicken α7 homomer-forming nicotinic receptor subunit which are predicted to enhance the negative charge at the negative subsite (loop D) of the ACh binding site.
Xenopus oocytes expressing wild-type α7 nicotinic receptors respond to imidacloprid with rapid inward currents. Imidacloprid and nitenpyram are partial agonists, whereas ACh, (−)-nicotine and (+)-epibatidine are full agonists.
Compared to wild-type α7, the mutant G189D and G189E receptors are much less sensitive to the insecticides, whereas their sensitivity to (−)-nicotine, ACh and (+)-epibatidine is only slightly reduced. In contrast, G189N and G189Q mutants are sensitive not only to ACh, (−)-nicotine and (+)-epibatidine, but also to the two insecticides. Thus reduction of the insecticide-sensitivity by the mutations G189D and G189E are attributed to an increase in negativity of loop D. Desnitro-imidacloprid (DN-IMI), an imidacloprid derivative lacking the nitro group is a potent agonist on the G189D and G189E mutants suggesting an important role of loop D in nicotinic receptor interactions with the nitro group of nitroguanidine insecticides.
British Journal of Pharmacology (2000) 130, 981–986; doi:10.1038/sj.bjp.0703374