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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Olivera-Bravo
Silvia
S
División de Fisiología, Departmento de Fisiología, Genética y Microbiología, Universidad de Alicante, E-03080 Alicante, Spain.
Ivorra
Isabel
I
Morales
Andrés
A
D000109:Acetylcholine / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D002093:Benzenaminium, 4,4'-(3-oxo-1,5-pentanediyl)bis(N,N-dimethyl-N-2-propenyl-), Dibromide / Q000008:administration & dosage / Q000494:pharmacology*; D001665:Binding Sites; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D003650:Decamethonium Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004491:Edrophonium / Q000008:administration & dosage / Q000494:pharmacology*; D004553:Electric Conductivity; D004594:Electrophysiology; D007473:Ion Channels / Q000187:drug effects; D009865:Oocytes / Q000187:drug effects; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000378:metabolism; D014101:Torpedo; D014981:Xenopus
D002800:Cholinesterase Inhibitors; D003650:Decamethonium Compounds; D007473:Ion Channels; D011978:Receptors, Nicotinic; D002093:Benzenaminium, 4,4'-(3-oxo-1,5-pentanediyl)bis(N,N-dimethyl-N-2-propenyl-), Dibromide; D004491:Edrophonium; C033019:decamethonium; D000109:Acetylcholine