The anthelmintic levamisole is an allosteric modulator of human neuronal nicotinic acetylcholine receptors.
L-[-]-2,3,5,6-Tetrahydro-6-phenylimidazo[2,1b]-thiazole hydrochloride (levamisole) is an anthelmintic that targets the nicotinic acetylcholine receptors of parasitic nematodes. We report here the effects of levamisole on human neuronal alpha 3 beta 2 and alpha 3 beta 4 nicotinic receptors, heterologously expressed in Xenopus oocytes and studied with the voltage clamp method. Applied alone, levamisole was a very weak partial agonist for the two subunit combinations. When co-applied with acetylcholine, micromolar concentrations of levamisole potentiated responses, while millimolar concentrations inhibited them; these effects were complex functions of both acetylcholine and levamisole concentrations. The differences in the levamisole effects on the two receptor combinations suggest that the effects are mediated by the beta subunit. Several combinations of agonist and anthelmintic gave the dual potentiation/inhibition behavior, suggesting that the modulatory effects are general. Levamisole inhibition showed macroscopic characteristics of open channel block. Several results led us to conclude that levamisole potentiation occurs through noncompetitive binding to the receptor. We propose pseudo-site binding for noncompetitive potentiation by levamisole.
Levandoski
Mark M
MM
Department of Chemistry, Grinnell College, P.O. Box 805, Grinnell, IA 50112, USA. levandos@grinnell.edu
Piket
Barbara
B
Chang
Jane
J
D000109:Acetylcholine / Q000008:administration & dosage / Q000493:pharmacokinetics; D000200:Action Potentials / Q000187:drug effects; D000494:Allosteric Regulation / Q000187:drug effects*; D000818:Animals; D004338:Drug Combinations; D004357:Drug Synergism; D005260:Female; D015870:Gene Expression; D006801:Humans; D007978:Levamisole / Q000008:administration & dosage / Q000493:pharmacokinetics*; D009474:Neurons / Q000737:chemistry; D009865:Oocytes / Q000187:drug effects; D018408:Patch-Clamp Techniques; D018075:RNA, Complementary / Q000187:drug effects; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000235:genetics; D014982:Xenopus laevis
D004338:Drug Combinations; D018075:RNA, Complementary; D011978:Receptors, Nicotinic; C419362:nicotinic receptor alpha3beta2; C403530:nicotinic receptor alpha3beta4; D007978:Levamisole; D000109:Acetylcholine