The noncompetitive inhibitor quinacrine modifies the desensitization kinetics of muscle acetylcholine receptors.
Quinacrine has been shown to act as a noncompetitive inhibitor of the nicotinic acetylcholine receptor (nAChR). However, its mechanism of action is still a matter of controversy. We analyzed in detail the action of quinacrine at both the single-channel and macroscopic current levels. The main effect of quinacrine is a profound concentration-dependent decrease in both the frequency of opening events and the duration of clusters elicited by high acetylcholine concentrations. Quinacrine also significantly increases (40-fold at 30 microM) the decay rate of macroscopic currents elicited by rapid perfusion of acetylcholine to outside-out patches. This decay is still well-described by a single exponential. Quinacrine has very little effect on the peak amplitude of the response, suggesting that it acts mainly on open channels. The recovery from desensitization after removal of acetylcholine is delayed in the presence of quinacrine. Results from both single-channel and macroscopic current recordings indicate that quinacrine increases the rate of nAChR desensitization and stabilizes the desensitized state. Interestingly, in equilibrium agonist-binding assays, quinacrine does not promote the typical high-affinity desensitized state. Thus, quinacrine seems to induce an intermediate state exhibiting the permeability but not the agonist binding properties of desensitization.
Spitzmaul
G
G
Instituto de Investigaciones Bioquímicas, Universidad Nacional del Sur-Consejo Nacional de Investigaciones Científicas y Técnicas, Bahía Blanca, Argentina.
Dilger
J P
JP
Bouzat
C
C
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D006801:Humans; D007700:Kinetics; D008564:Membrane Potentials; D051379:Mice; D009132:Muscles / Q000187:drug effects* / Q000502:physiology; D011796:Quinacrine / Q000494:pharmacology*; D011950:Receptors, Cholinergic / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D013997:Time Factors; D014162:Transfection
D011950:Receptors, Cholinergic; D011796:Quinacrine; D000109:Acetylcholine