Competitive Potentiation of Acetylcholine Effects on Neuronal Nicotinic Receptors by Acetylcholinesterase-Inhibiting Drugs.

Autor: Zwart, Ruud, van Kleef, Regina G.D.M., Gotti, Cecilia, Smulders, Chantal J.G.M., Vijverberg, Henk P.M.
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Zdroj: Journal of Neurochemistry; Dec2000, Vol. 75 Issue 6, p2492, 9p, 3 Diagrams, 2 Charts, 4 Graphs
Abstrakt: Abstract: The effects of the acetylcholinesterase inhibi-tors physostigmine and tacrine on a4b2 and a4b4 sub-types of neuronal nicotinic acetylcholine (ACh) receptors, expressed in Xenopus laevis oocytes, have been investigated. In voltage-clamp experiments low concentrations of physostigmine and tacrine potentiate ion currents in-duced by low concentrations of ACh, whereas at high concentrations they inhibit ACh-induced ion currents. These dual effects result in bell-shaped concentration-effect curves. Physostigmine and tacrine, by themselves, do not act as nicotinic receptor agonists. The larger po-tentiation is observed with 10 µM physostigmine on a4b4 nicotinic receptors and amounts to 70% at 1 µM ACh. The mechanism underlying the effects of physostigmine on a4b4 ACh receptors has been investigated in detail. Potentiation of ACh-induced ion current by low concen-trations of physostigmine is surmounted at elevated con-centrations of ACh, indicating that this is a competitive effect. Conversely, inhibition of ACh-induced ion current by high concentrations of physostigmine is not sur-mounted at high concentrations of ACh, and this effect appears mainly due to noncompetitive, voltage-depen-dent ion channel block. Radioligand binding experiments demonstrating displacement of the nicotinic receptor ag-onist 125 I-epibatidine from its recognition sites on a4b4 ACh receptors by physostigmine confirm that physostig-mine is a competitive ligand at these receptors. A two-site equilibrium receptor occupation model, combined with noncompetitive ion channel block, accounts for the dual effects of physostigmine and tacrine on ACh-in-duced ion currents. It is concluded that these acetylcho-linesterase- inhibiting drugs interact with the ACh recog-nition sites and are coagonists of ACh on a4-containing nicotinic ACh receptors. Key Words: Neuronal nicotinic acetylcholine receptor--Acetylcholinesterase inhibitor--Tacrine--Physostigmine. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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