alpha-conotoxin MrIC is a biased agonist at alpha(7) nicotinic acetylcholine receptors

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.