title: α-Conotoxin MrIC is a biased agonist at α7 nicotinic acetylcholine receptors.
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.
authors: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia.
authors: Alexander
authors: A
authors: Mueller
authors: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia.
authors: Hana
authors: H
authors: Starobova
authors: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia.
authors: Marco C
authors: MC
authors: Inserra
authors: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia.
authors: Ai-Hua
authors: AH
authors: Jin
authors: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia.
authors: Jennifer R
authors: JR
authors: Deuis
authors: Institut des Biomolécules Max Mousseron, UMR 5247, Université Montpellier 2-CNRS, Place Eugène Bataillon, Montpellier Cedex 5 34095, France.
authors: Sébastien
authors: S
authors: Dutertre
authors: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia.
authors: Richard J
authors: RJ
authors: Lewis
authors: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia.
authors: Paul F
authors: PF
authors: Alewood
authors: Centre for Biodiscovery and Molecular Development of Therapeutics, AITHM, James Cook University, Queensland 4878, Australia.
authors: Norelle L
authors: NL
authors: Daly
authors: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia; School of Pharmacy, The University of Queensland, Woolloongabba, Queensland 4102, Australia. Electronic address: i.vetter@uq.edu.au.
authors: Irina
authors: I
authors: Vetter
mesh_terms: D045744:Cell Line, Tumor; D020916:Conotoxins / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000819:agonists*
chemical_list: D020916:Conotoxins; C587016:MrIC conotoxin, Conus marmoreus; D064569:alpha7 Nicotinic Acetylcholine Receptor
keywords: Allosteric; Alpha7; Conotoxin; NMR; Nicotinic