British Journal of Pharmacology 2007-08-01

Diverse inhibitory actions of quaternary ammonium cholinesterase inhibitors on Torpedo nicotinic ACh receptors transplanted to Xenopus oocytes.

Silvia Olivera-Bravo, Isabel Ivorra, Andrés Morales

Index: Br. J. Pharmacol. 151(8) , 1280-92, (2007)

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Abstract

This work was aimed at comparing and analysing the effects and mechanisms of action of the quaternary ammonium cholinesterase inhibitors (QChEIs) BW284c51, decamethonium and edrophonium, on nicotinic ACh receptor (nAChR) function.nAChRs purified from Torpedo electroplax were transplanted to oocytes and currents elicited by ACh (I(ACh)) either alone or in presence of these QChEIs were recorded.None of the QChEIs, by itself, elicited changes in membrane conductance; however, when co-applied with ACh, all of them decreased I(ACh) in a concentration-dependent way. The mechanisms of nAChR inhibition were different for these QChEIs. BW284c51 blockade was non-competitive and voltage-dependent, although it also affected the n(H) of the dose-response curve. By contrast, decamethonium and edrophonium inhibition, at -60 mV, was apparently competitive and did not modify either desensitisation or n(H). Decamethonium effects were voltage-independent and washed out slowly after its removal; by contrast, edrophonium blockade had strong voltage dependence and its effects disappeared quickly after its withdrawal. Analysis of the voltage-dependent blockade indicated that BW284c51 bound to a shallow site into the channel pore, whereas edrophonium bound to a deeper locus. Accordingly, additive inhibitory effects on I(ACh) were found among any pairs of these QChEIs.The tested QChEIs bound to the nAChR at several and different loci, which might account for their complex inhibitory behaviour, acting both as allosteric effectors and, in the case of BW284c51 and edrophonium, as open channel blockers.