Received for publication December 21, 2007.
Revised April 5, 2008.
Accepted for publication April 29, 2008.

Morantel Allosterically Enhances Channel Gating of Neuronal Nicotinic Acetylcholine 32 Receptors

Abstract

We studied allosteric potentiation of rat 32 neuronal nicotinic acetylcholine receptors (nAChRs) by the anthelmintic compound morantel. Macroscopic currents evoked by ACh from nAChRs expressed in Xenopus oocytes increase up to eight-fold in the presence of low concentrations of morantel ( 10 µM); the magnitude of the potentiation depends on both agonist and modulator concentrations. Importantly, the potentiated currents exceed the maximum currents achieved by saturating (mM) concentrations of agonist. Studies of macroscopic currents elicited by prolonged drug applications (100 - 300 s) indicate that morantel does not increase 32 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 classical competitive antagonist dihydro--erythroidine inhibits morantel-evoked currents noncompetitively, indicating that morantel does not bind to the canonical ACh binding sites.

Key words: Nicotinic cholinergic, Ion channel regulation, Single channel kinetics