Document Detail

Structure-activity relationships of acetylcholine derivatives with Lucilia cuprina nicotinic acetylcholine receptor α1 and α2 subunits in chicken β2 subunit hybrid receptors in comparison with chicken nicotinic acetylcholine receptor α4/β2.
MedLine Citation:
PMID:  23331538     Owner:  NLM     Status:  Publisher    
Insect nicotinic acetylcholine (ACh) receptors (nAChRs) are the targets of several insecticide classes. In the present study, we report the gene identification and cloning of nAChR α1 and α2 subunits (Lcα1 and Lcα2) from the sheep blowfly Lucilia cuprina. Xenopus oocytes voltage clamp experiments as hybrids with the chicken β2 nAChR (Ggβ2) subunit resulted in ACh-gated ion channels with distinct dose-response curves for Lcα1/Ggβ2 (effective concentration 50% [EC(50) ] = 80 nM; n(H)  = 1.05), and Lcα2/Ggβ2 (EC(50)  = 5.37 μM, n(H)  = 1.46). The neonicotinoid imidacloprid was a potent agonist for the α-bungarotoxin-sensitive Lcα1/Ggβ2 (EC(50) ∼ 20 nM), while the α-bungarotoxin-resistant Lcα2/Ggβ2 showed a 30-fold lower sensitivity to this insecticide (EC(50)  = 0.62 μM). Thirteen close derivatives of ACh were analysed in EC(50) , Hill coefficient and maximum current (relative to ACh) determinations for Lcα1/Ggβ2 and Lcα2/Ggβ2 and the chicken Ggα4/Ggβ2 nAChRs, and comparisons relative to ACh allowed the definition of novel structure-activity and structure-selectivity relationships. In the case of N-ethyl-acetylcholine, the EC(50) of the chicken Ggα4/Ggβ2 rose by a factor of 1000, while for both Lcα1/Ggβ2 and Lcα2/Ggβ2, potency remained unchanged. Further derivatives with insect nAChR selectivity potential were acetyl-α-methylcholine and trimethyl-(3-methoxy-3-oxopropyl)ammonium, followed by acetylhomocholine and trimethyl-(4-oxopentyl) ammonium. Our results may provide guidance for the identification or design of insect-specific nAChR agonists using structure-based or in silico methods.
H Dederer; M Berger; T Meyer; M Werr; T Ilg
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-1-21
Journal Detail:
Title:  Insect molecular biology     Volume:  -     ISSN:  1365-2583     ISO Abbreviation:  Insect Mol. Biol.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-21     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9303579     Medline TA:  Insect Mol Biol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
© 2013 Royal Entomological Society.
MSD Animal Health Innovation GmbH, Schwabenheim, Germany.
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