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Morantel Allosterically Enhances Channel Gating of Neuronal Nicotinic Acetylcholine 3β2 Receptors

Department of Chemistry, Grinnell College, Grinnell, Iowa (T.Y.W., C.M.S., M.M.L.); and Receptor Biology Laboratory, Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota (S.M.S.)

We studied allosteric potentiation of rat 3β2 neuronal nicotinic acetylcholine receptors (nAChRs) by the anthelmintic compound morantel. Macroscopic currents evoked by acetylcholine (ACh) from nAChRs expressed in Xenopus laevis oocytes increase up to 8-fold in the presence of low concentrations of morantel (10 µM); the magnitude of the potentiation depends on both agonist and modulator concentrations. It is noteworthy that the potentiated currents exceed the maximum currents achieved by saturating (millimolar) concentrations of agonist. Studies of macroscopic currents elicited by prolonged drug applications (100-300 s) indicate that morantel does not increase 3β2 receptor activity by reducing slow (1 s) desensitization. Instead, using outside-out patch-clamp recordings, we demonstrate that morantel increases the frequency of single-channel openings and alters the bursting characteristics of the openings in a manner consistent with enhanced channel gating; these results quantitatively explain the macroscopic current potentiation. Morantel is a very weak agonist alone, but we show that the classic competitive antagonist dihydro-β-erythroidine inhibits morantel-evoked currents noncompetitively, indicating that morantel does not bind to the canonical ACh binding sites.

Address correspondence to: Mark M. Levandoski, Department of Chemistry, Box 805, Grinnell College, Grinnell, IA 50112. E-mail: levandos{at}grinnell.edu