PT  - JOURNAL ARTICLE
AU  - Tse-Yu Wu
AU  - Caleb M. Smith
AU  - Steven M. Sine
AU  - Mark M. Levandoski
TI  - Morantel Allosterically Enhances Channel Gating of Neuronal Nicotinic Acetylcholine α3β2 Receptors
AID  - 10.1124/mol.107.044388
DP  - 2008 Aug 01
TA  - Molecular Pharmacology
PG  - 466--475
VI  - 74
IP  - 2
4099  - http://molpharm.aspetjournals.org/content/74/2/466.short
4100  - http://molpharm.aspetjournals.org/content/74/2/466.full
SO  - Mol Pharmacol2008 Aug 01; 74
AB  - We studied allosteric potentiation of rat α3β2 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 α3β2 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. The American Society for Pharmacology and Experimental Therapeutics