Bastien Dutertre, Sé, Mueller, Alexander, Starobova, Hana, Inserra, Marco, Jin, Ai-Hua, Deuis, Jennifer, Dutertre, Sébastien, Lewis, Richard, Alewood, Paul, Daly, Norelle, Vetter, Irina, Institut for Molecular Bioscience, University of Southern Queensland (USQ), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), Institute of Molecular Bioscience, and University of Queensland [Brisbane]
MrIC is a recently described selective agonist of endogenously expressed alpha 7 nAChR. In this study, we further characterize the pharmacological activity of MrIC using Ca2+ imaging approaches in SH-SY5Y cells endogenously expressing alpha 7 nAChR and demonstrate that MrIC exclusively activates alpha 7 nAChR modulated by type II positive allosteric modulators, including PNU120596. MrIC was a full agonist at PNU120596-modulated alpha 7 nAChR compared with choline, albeit with slower kinetics, but failed to elicit a Ca2+ response in the absence of PNU120596. Interestingly, the NMR structure of MrIC showed a typical 4/7 alpha-conotoxin fold, indicating that its unusual pharmacological activity is likely sequence-dependent. Overall, our results suggest that MrIC acts as a biased agonist that can only activate alpha 7 nAChR modified by type II positive allosteric modulators, and thus represents a valuable tool to probe the pharmacological properties of this important ion channel. (C) 2015 Elsevier Inc. All rights reserved.