α-Conotoxin MrIC is a biased agonist at α7 nicotinic acetylcholine receptors.
Identifieur interne : 002624 ( Main/Exploration ); précédent : 002623; suivant : 002625α-Conotoxin MrIC is a biased agonist at α7 nicotinic acetylcholine receptors.
Auteurs : Alexander Mueller [Australie] ; Hana Starobova [Australie] ; Marco C. Inserra [Australie] ; Ai-Hua Jin [Australie] ; Jennifer R. Deuis [Australie] ; Sébastien Dutertre [France] ; Richard J. Lewis [Australie] ; Paul F. Alewood [Australie] ; Norelle L. Daly [Australie] ; Irina Vetter [Australie]Source :
- Biochemical pharmacology [ 1873-2968 ] ; 2015.
Descripteurs français
- KwdFr :
- MESH :
- agonistes : Récepteur nicotinique de l'acétylcholine alpha7.
- pharmacologie : Conotoxines.
- Conotoxines, Humains, Lignée cellulaire tumorale, Spectroscopie par résonance magnétique.
English descriptors
- KwdEn :
- MESH :
- chemical , agonists : alpha7 Nicotinic Acetylcholine Receptor.
- chemical , chemistry : Conotoxins.
- chemical , pharmacology : Conotoxins.
- Cell Line, Tumor, Humans, Magnetic Resonance Spectroscopy.
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.
DOI: 10.1016/j.bcp.2015.01.011
PubMed: 25646788
Affiliations:
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Deuis</name><affiliation wicri:level="1"><nlm:affiliation>Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072</wicri:regionArea><wicri:noRegion>Queensland 4072</wicri:noRegion></affiliation></author><author><name sortKey="Dutertre, Sebastien" sort="Dutertre, Sebastien" uniqKey="Dutertre S" first="Sébastien" last="Dutertre">Sébastien Dutertre</name><affiliation wicri:level="1"><nlm:affiliation>Institut des Biomolécules Max Mousseron, UMR 5247, Université Montpellier 2-CNRS, Place Eugène Bataillon, Montpellier Cedex 5 34095, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Institut des Biomolécules Max Mousseron, UMR 5247, Université Montpellier 2-CNRS, Place Eugène Bataillon, Montpellier Cedex 5 34095</wicri:regionArea><wicri:noRegion>34095</wicri:noRegion><wicri:noRegion>34095</wicri:noRegion></affiliation></author><author><name sortKey="Lewis, Richard J" sort="Lewis, Richard J" uniqKey="Lewis R" first="Richard J" last="Lewis">Richard J. Lewis</name><affiliation wicri:level="1"><nlm:affiliation>Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072</wicri:regionArea><wicri:noRegion>Queensland 4072</wicri:noRegion></affiliation></author><author><name sortKey="Alewood, Paul F" sort="Alewood, Paul F" uniqKey="Alewood P" first="Paul F" last="Alewood">Paul F. Alewood</name><affiliation wicri:level="1"><nlm:affiliation>Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072</wicri:regionArea><wicri:noRegion>Queensland 4072</wicri:noRegion></affiliation></author><author><name sortKey="Daly, Norelle L" sort="Daly, Norelle L" uniqKey="Daly N" first="Norelle L" last="Daly">Norelle L. Daly</name><affiliation wicri:level="1"><nlm:affiliation>Centre for Biodiscovery and Molecular Development of Therapeutics, AITHM, James Cook University, Queensland 4878, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Centre for Biodiscovery and Molecular Development of Therapeutics, AITHM, James Cook University, Queensland 4878</wicri:regionArea><wicri:noRegion>Queensland 4878</wicri:noRegion></affiliation></author><author><name sortKey="Vetter, Irina" sort="Vetter, Irina" uniqKey="Vetter I" first="Irina" last="Vetter">Irina Vetter</name><affiliation wicri:level="1"><nlm:affiliation>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.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>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</wicri:regionArea><wicri:noRegion>Queensland 4102</wicri:noRegion></affiliation></author></analytic><series><title level="j">Biochemical pharmacology</title><idno type="eISSN">1873-2968</idno><imprint><date when="2015" type="published">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Cell Line, Tumor</term><term>Conotoxins (chemistry)</term><term>Conotoxins (pharmacology)</term><term>Humans</term><term>Magnetic Resonance Spectroscopy</term><term>alpha7 Nicotinic Acetylcholine Receptor (agonists)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Conotoxines ()</term><term>Conotoxines (pharmacologie)</term><term>Humains</term><term>Lignée cellulaire tumorale</term><term>Récepteur nicotinique de l'acétylcholine alpha7 (agonistes)</term><term>Spectroscopie par résonance magnétique</term></keywords><keywords scheme="MESH" type="chemical" qualifier="agonists" xml:lang="en"><term>alpha7 Nicotinic Acetylcholine Receptor</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Conotoxins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Conotoxins</term></keywords><keywords scheme="MESH" qualifier="agonistes" xml:lang="fr"><term>Récepteur nicotinique de l'acétylcholine alpha7</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Conotoxines</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Cell Line, Tumor</term><term>Humans</term><term>Magnetic Resonance Spectroscopy</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Conotoxines</term><term>Humains</term><term>Lignée cellulaire tumorale</term><term>Spectroscopie par résonance magnétique</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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.</div></front></TEI><affiliations><list><country><li>Australie</li><li>France</li></country></list><tree><country name="Australie"><noRegion><name sortKey="Mueller, Alexander" sort="Mueller, Alexander" uniqKey="Mueller A" first="Alexander" last="Mueller">Alexander Mueller</name></noRegion><name sortKey="Alewood, Paul F" sort="Alewood, Paul F" uniqKey="Alewood P" first="Paul F" last="Alewood">Paul F. Alewood</name><name sortKey="Daly, Norelle L" sort="Daly, Norelle L" uniqKey="Daly N" first="Norelle L" last="Daly">Norelle L. Daly</name><name sortKey="Deuis, Jennifer R" sort="Deuis, Jennifer R" uniqKey="Deuis J" first="Jennifer R" last="Deuis">Jennifer R. Deuis</name><name sortKey="Inserra, Marco C" sort="Inserra, Marco C" uniqKey="Inserra M" first="Marco C" last="Inserra">Marco C. Inserra</name><name sortKey="Jin, Ai Hua" sort="Jin, Ai Hua" uniqKey="Jin A" first="Ai-Hua" last="Jin">Ai-Hua Jin</name><name sortKey="Lewis, Richard J" sort="Lewis, Richard J" uniqKey="Lewis R" first="Richard J" last="Lewis">Richard J. Lewis</name><name sortKey="Starobova, Hana" sort="Starobova, Hana" uniqKey="Starobova H" first="Hana" last="Starobova">Hana Starobova</name><name sortKey="Vetter, Irina" sort="Vetter, Irina" uniqKey="Vetter I" first="Irina" last="Vetter">Irina Vetter</name></country><country name="France"><noRegion><name sortKey="Dutertre, Sebastien" sort="Dutertre, Sebastien" uniqKey="Dutertre S" first="Sébastien" last="Dutertre">Sébastien Dutertre</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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