Citation

Näreoja K, Kukkonen J, Rondinelli S, Toivola D, Meriluoto J, Näsman J. Br. J. Pharmacol. 2011; 164(2b): 538-550.

Affiliation

Department of Biosciences, Biochemistry, Åbo Akademi University, Turku, Finland Department of Veterinary Biosciences, Biochemistry and Cell Biology, University of Helsinki, Helsinki, Finland Minerva Institute for Medical Research, Helsinki, Finland Department of Biosciences, Cell biology, Åbo Akademi University, Turku, Finland.

Copyright

(Copyright © 2011, John Wiley and Sons)

DOI

10.1111/j.1476-5381.2011.01468.x

PMID

21557730

PMCID

PMC3188914

Abstract

Background and purpose: Muscarinic toxins (MTs) are snake venom peptides named for their ability to interfere with ligand binding to muscarinic acetylcholine receptors (mAChRs). Recent data infer that these toxins may have other G-protein coupled receptor targets than the mAChRs. The purpose of this study was to systematically investigate the interactions of MTs with the adrenoceptor family members. Experimental approach: We studied the interaction of four common MTs, MT1, -3, -7 and -α with cloned receptors expressed in insect cells by radioligand binding. Toxins showing modest to high affinity interactions with adrenoceptors were additionally tested for effects on functional receptor responses by way of inhibition of agonist-induced Ca(2+) increases. Key results: All MTs behaved non-competitively in radioligand displacement binding. MT1 displayed higher binding affinity for the human α(2B) -adrenoceptor (IC(50) = 2.3 nM) as compared to muscarinic receptors (IC(50) ≥ 100 nM). MT3 appeared to have a broad spectrum of targets showing high affinity binding (IC(50) = 1-10 nM) to M(4) mAChR, α(1A) -, α(1D) - and α(2A) -adrenoceptors, and lower affinity binding (IC(50) ≥ 25 nM) to α(1B) - and α(2C) -adrenoceptors and M(1) mAChR. MT7 did not detectably bind to other receptors than M(1) , and MTα was specific for the α(2B) -adrenoceptor. None of the toxins showed effects on β(1) - or β(2) -adrenoceptors. Conclusions and implications: Some of the MTs previously found to interact predominantly with mAChRs were shown to bind with high affinity to selected adrenoceptor subtypes. This renders these peptide toxins useful for engineering selective ligands to target various adrenoceptors.

Language: en