Morphine Binds Creatine Kinase B and Inhibits Its Activity
Morphine is an analgesic alkaloid used to relieve severe pain, and irreversible binding of morphine to specific unknown proteins has been previously observed. In the brain, changes in the expression of energy metabolism enzymes contribute to behavioral abnormalities during chronic morphine treatment...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-12-01
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| Series: | Frontiers in Cellular Neuroscience |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fncel.2018.00464/full |
| _version_ | 1818177464512282624 |
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| author | Ivan Weinsanto Jinane Mouheiche Alexis Laux-Biehlmann Alexis Laux-Biehlmann François Delalande Arnaud Marquette Virginie Chavant Virginie Chavant Florian Gabel Sarah Cianferani Alexandre Charlet Marie-Odile Parat Yannick Goumon Yannick Goumon |
| author_facet | Ivan Weinsanto Jinane Mouheiche Alexis Laux-Biehlmann Alexis Laux-Biehlmann François Delalande Arnaud Marquette Virginie Chavant Virginie Chavant Florian Gabel Sarah Cianferani Alexandre Charlet Marie-Odile Parat Yannick Goumon Yannick Goumon |
| author_sort | Ivan Weinsanto |
| collection | DOAJ |
| description | Morphine is an analgesic alkaloid used to relieve severe pain, and irreversible binding of morphine to specific unknown proteins has been previously observed. In the brain, changes in the expression of energy metabolism enzymes contribute to behavioral abnormalities during chronic morphine treatment. Creatine kinase B (CK-B) is a key enzyme involved in brain energy metabolism. CK-B also corresponds to the imidazoline-binding protein I2 which binds dopamine (a precursor of morphine biosynthesis) irreversibly. Using biochemical approaches, we show that recombinant mouse CK-B possesses a μM affinity for morphine and binds to morphine in vitro. The complex formed by CK-B and morphine is resistant to detergents, reducing agents, heat treatment and SDS-polyacrylamide gel electrophoresis (SDS-PAGE). CK-B-derived peptides CK-B1–75 and CK-B184–258 were identified as two specific morphine binding-peptides. In vitro, morphine (1–100 μM) significantly reduces recombinant CK-B enzymatic activity. Accordingly, in vivo morphine administration (7.5 mg/kg, i.p.) to mice significantly decreased brain extract CK-B activity compared to saline-treated animals. Together, these results show that morphine strongly binds CK-B and inhibits its activity in vitro and in vivo. |
| first_indexed | 2024-12-11T20:32:30Z |
| format | Article |
| id | doaj.art-bc95e2d0e67545c99ea409795946c48d |
| institution | Directory Open Access Journal |
| issn | 1662-5102 |
| language | English |
| last_indexed | 2024-12-11T20:32:30Z |
| publishDate | 2018-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cellular Neuroscience |
| spelling | doaj.art-bc95e2d0e67545c99ea409795946c48d2022-12-22T00:51:45ZengFrontiers Media S.A.Frontiers in Cellular Neuroscience1662-51022018-12-011210.3389/fncel.2018.00464418894Morphine Binds Creatine Kinase B and Inhibits Its ActivityIvan Weinsanto0Jinane Mouheiche1Alexis Laux-Biehlmann2Alexis Laux-Biehlmann3François Delalande4Arnaud Marquette5Virginie Chavant6Virginie Chavant7Florian Gabel8Sarah Cianferani9Alexandre Charlet10Marie-Odile Parat11Yannick Goumon12Yannick Goumon13Institut des Neurosciences Cellulaires et Intégratives, CNRS UPR3212 and Université de Strasbourg, Strasbourg, FranceInstitut des Neurosciences Cellulaires et Intégratives, CNRS UPR3212 and Université de Strasbourg, Strasbourg, FranceInstitut des Neurosciences Cellulaires et Intégratives, CNRS UPR3212 and Université de Strasbourg, Strasbourg, FranceLaboratoire de Spectrométrie de Masse BioOrganique, IPHC-DSA, CNRS UMR7178 and Université de Strasbourg, Strasbourg, FranceLaboratoire de Spectrométrie de Masse BioOrganique, IPHC-DSA, CNRS UMR7178 and Université de Strasbourg, Strasbourg, FranceCNRS UMR7177 and Université de Strasbourg, Strasbourg, FranceInstitut des Neurosciences Cellulaires et Intégratives, CNRS UPR3212 and Université de Strasbourg, Strasbourg, FranceMass Spectrometry Facilities of the CNRS UPR3212, Strasbourg, FranceInstitut des Neurosciences Cellulaires et Intégratives, CNRS UPR3212 and Université de Strasbourg, Strasbourg, FranceLaboratoire de Spectrométrie de Masse BioOrganique, IPHC-DSA, CNRS UMR7178 and Université de Strasbourg, Strasbourg, FranceInstitut des Neurosciences Cellulaires et Intégratives, CNRS UPR3212 and Université de Strasbourg, Strasbourg, FranceSchool of Pharmacy, University of Queensland, PACE, Woolloongabba, QLD, AustraliaInstitut des Neurosciences Cellulaires et Intégratives, CNRS UPR3212 and Université de Strasbourg, Strasbourg, FranceMass Spectrometry Facilities of the CNRS UPR3212, Strasbourg, FranceMorphine is an analgesic alkaloid used to relieve severe pain, and irreversible binding of morphine to specific unknown proteins has been previously observed. In the brain, changes in the expression of energy metabolism enzymes contribute to behavioral abnormalities during chronic morphine treatment. Creatine kinase B (CK-B) is a key enzyme involved in brain energy metabolism. CK-B also corresponds to the imidazoline-binding protein I2 which binds dopamine (a precursor of morphine biosynthesis) irreversibly. Using biochemical approaches, we show that recombinant mouse CK-B possesses a μM affinity for morphine and binds to morphine in vitro. The complex formed by CK-B and morphine is resistant to detergents, reducing agents, heat treatment and SDS-polyacrylamide gel electrophoresis (SDS-PAGE). CK-B-derived peptides CK-B1–75 and CK-B184–258 were identified as two specific morphine binding-peptides. In vitro, morphine (1–100 μM) significantly reduces recombinant CK-B enzymatic activity. Accordingly, in vivo morphine administration (7.5 mg/kg, i.p.) to mice significantly decreased brain extract CK-B activity compared to saline-treated animals. Together, these results show that morphine strongly binds CK-B and inhibits its activity in vitro and in vivo.https://www.frontiersin.org/article/10.3389/fncel.2018.00464/fullmorphinecomplexligand-binding proteincreatine kinasehigh affinity |
| spellingShingle | Ivan Weinsanto Jinane Mouheiche Alexis Laux-Biehlmann Alexis Laux-Biehlmann François Delalande Arnaud Marquette Virginie Chavant Virginie Chavant Florian Gabel Sarah Cianferani Alexandre Charlet Marie-Odile Parat Yannick Goumon Yannick Goumon Morphine Binds Creatine Kinase B and Inhibits Its Activity Frontiers in Cellular Neuroscience morphine complex ligand-binding protein creatine kinase high affinity |
| title | Morphine Binds Creatine Kinase B and Inhibits Its Activity |
| title_full | Morphine Binds Creatine Kinase B and Inhibits Its Activity |
| title_fullStr | Morphine Binds Creatine Kinase B and Inhibits Its Activity |
| title_full_unstemmed | Morphine Binds Creatine Kinase B and Inhibits Its Activity |
| title_short | Morphine Binds Creatine Kinase B and Inhibits Its Activity |
| title_sort | morphine binds creatine kinase b and inhibits its activity |
| topic | morphine complex ligand-binding protein creatine kinase high affinity |
| url | https://www.frontiersin.org/article/10.3389/fncel.2018.00464/full |
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