Mueller, Alexander, Starobova, Hana, Inserra, Marco C., Jin, Ai-Hua, Deuis, Jennifer R., Dutertre, Sébastien, Lewis, Richard J., Alewood, Paul F., Daly, Norelle L., and Vetter, Irina (2015) α-conotoxin MrIC is a biased agonist at α7 nicotinic acetylcholine receptors. Biochemical Pharmacology, 94 (2). pp. 155-163.

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Abstract

MrIC is a recently described selective agonist of endogenously expressed α7 nAChR. In this study, we further characterize the pharmacological activity of MrIC using Ca^2+ imaging approaches in SH-SY5Y cells endogenously expressing α7 nAChR and demonstrate that MrIC exclusively activates α7 nAChR modulated by type II positive allosteric modulators, including PNU120596. MrIC was a full agonist at PNU120596-modulated α7 nAChR compared with choline, albeit with slower kinetics, but failed to elicit a Ca^2+ response in the absence of PNU120596. Interestingly, the NMR structure of MrIC showed a typical 4/7 α-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 α7 nAChR modified by type II positive allosteric modulators, and thus represents a valuable tool to probe the pharmacological properties of this important ion channel.

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