2. Academic Validation
  3. α-Conotoxin MrIC is a biased agonist at α7 nicotinic acetylcholine receptors

α-Conotoxin MrIC is a biased agonist at α7 nicotinic acetylcholine receptors

  • Biochem Pharmacol. 2015 Mar 15;94(2):155-63. doi: 10.1016/j.bcp.2015.01.011.
Alexander Mueller 1,  Hana Starobova 1,  Marco C Inserra 1,  Ai-Hua Jin 1,  Jennifer R Deuis 1,  Sébastien Dutertre 2,  Richard J Lewis 1,  Paul F Alewood 1,  Norelle L Daly 3,  Irina Vetter 4
Affiliations

Affiliations

  • 1 Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia.
  • 2 Institut des Biomolécules Max Mousseron, UMR 5247, Université Montpellier 2-CNRS, Place Eugène Bataillon, Montpellier Cedex 5 34095, France.
  • 3 Centre for Biodiscovery and Molecular Development of Therapeutics, AITHM, James Cook University, Queensland 4878, Australia.
  • 4 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: [email protected].
PMID: 25646788 DOI: 10.1016/j.bcp.2015.01.011
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.

Keywords

Allosteric; Alpha7; Conotoxin; NMR; Nicotinic.

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