Role of loop D of the alpha 7 nicotinic acetylcholine receptor in its interaction with the insecticide imidacloprid and related neonicotinoids

Citation
K. Matsuda et al., Role of loop D of the alpha 7 nicotinic acetylcholine receptor in its interaction with the insecticide imidacloprid and related neonicotinoids, BR J PHARM, 130(5), 2000, pp. 981-986
Citations number
17
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology & Toxicology
Journal title
BRITISH JOURNAL OF PHARMACOLOGY
ISSN journal
0007-1188 → ACNP
Volume
130
Issue
5
Year of publication
2000
Pages
981 - 986
Database
ISI
SICI code
0007-1188(200007)130:5<981:ROLDOT>2.0.ZU;2-P
Abstract
1 The nitroguanidine insecticide imidacloprid along with a second generatio n of related compounds including nitenpyram, all nicotinic acetylcholine (A Ch) receptor ligands, are used increasingly in many countries. Site-directe d mutagenesis and heterologous expression in Xenopus laevis oocytes have be en deployed to investigate mutants (G189D and G189E) of the chicken alpha 7 homomer-forming nicotinic receptor subunit which are predicted to enhance the negative charge at the negative subsite (loop D) of the ACh binding sit e. 2 Xenopus oocytes expressing wild-type a7 nicotinic receptors respond to im idacloprid with rapid inward currents. Imidacloprid and nitenpyram are part ial agonists, whereas ACh, (-)-nicotine and (+)-epibatidine are full agonis ts. 3 Compared to wild-type alpha 7, the mutant G189D and G189E receptors are m uch less sensitive to the insecticides, whereas their sensitivity to (-)-ni cotine, ACh and (+)-epibatidine is only slightly reduced. In contrast, G189 N and G189Q mutants are sensitive not only to ACh, (-)-nicotine and (+)-epi batidine, but also to the two insecticides. Thus reduction of the insectici de-sensitivity by the mutations G189D and G189E are attributed to an increa se in negativity of loop D. Desnitro-imidacloprid (DN-IMI), an imidacloprid derivative lacking the nitro group is a potent agonist on the G189D and G1 89E mutants suggesting an important role of loop D in nicotinic receptor in teractions with the nitro group of nitroguanidine insecticides.