Pharmacological Characterization of the Mechanisms Involved in Delayed Calcium Deregulation in SH-SY5Y Cells Challenged with Methadone
Previously, we have shown that SH-SY5Y cells exposed to high concentrations of methadone died due to a necrotic-like cell death mechanism related to delayed calcium deregulation (DCD). In this study, we show that, in terms of their Ca2+ responses to 0.5 mM methadone, SH-SY5Y cells can be pooled into...
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| Format: | Article |
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2012-01-01
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| Series: | International Journal of Cell Biology |
| Online Access: | http://dx.doi.org/10.1155/2012/642482 |
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| author | Sergio Perez-Alvarez Maria E. Solesio Maria D. Cuenca-Lopez Raquel M. Melero-Fernández de Mera Carlos Villalobos Hanna Kmita Maria F. Galindo Joaquin Jordán |
| author_facet | Sergio Perez-Alvarez Maria E. Solesio Maria D. Cuenca-Lopez Raquel M. Melero-Fernández de Mera Carlos Villalobos Hanna Kmita Maria F. Galindo Joaquin Jordán |
| author_sort | Sergio Perez-Alvarez |
| collection | DOAJ |
| description | Previously, we have shown that SH-SY5Y cells exposed to high concentrations of methadone died due to a necrotic-like cell death mechanism related to delayed calcium deregulation (DCD). In this study, we show that, in terms of their Ca2+ responses to 0.5 mM methadone, SH-SY5Y cells can be pooled into four different groups. In a broad pharmacological survey, the relevance of different Ca2+-related mechanisms on methadone-induced DCD was investigated including extracellular calcium, L-type Ca2+ channels, μ-opioid receptor, mitochondrial inner membrane potential, mitochondrial ATP synthesis, mitochondrial Ca2+/2Na+-exchanger, reactive oxygen species, and mitochondrial permeability transition. Only those compounds targeting mitochondria such as oligomycin, FCCP, CGP 37157, and cyclosporine A were able to amend methadone-induced Ca2+ dyshomeostasis suggesting that methadone induces DCD by modulating the ability of mitochondria to handle Ca2+. Consistently, mitochondria became dramatically shorter and rounder in the presence of methadone. Furthermore, analysis of oxygen uptake by isolated rat liver mitochondria suggested that methadone affected mitochondrial Ca2+ uptake in a respiratory substrate-dependent way. We conclude that methadone causes failure of intracellular Ca2+ homeostasis, and this effect is associated with morphological and functional changes of mitochondria. Likely, this mechanism contributes to degenerative side effects associated with methadone treatment. |
| format | Article |
| id | doaj-art-da89ce432d9042e0a302b91ec3d8928b |
| institution | Kabale University |
| issn | 1687-8876 1687-8884 |
| language | English |
| publishDate | 2012-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | International Journal of Cell Biology |
| spelling | doaj-art-da89ce432d9042e0a302b91ec3d8928b2025-02-03T06:01:22ZengWileyInternational Journal of Cell Biology1687-88761687-88842012-01-01201210.1155/2012/642482642482Pharmacological Characterization of the Mechanisms Involved in Delayed Calcium Deregulation in SH-SY5Y Cells Challenged with MethadoneSergio Perez-Alvarez0Maria E. Solesio1Maria D. Cuenca-Lopez2Raquel M. Melero-Fernández de Mera3Carlos Villalobos4Hanna Kmita5Maria F. Galindo6Joaquin Jordán7Neuropharmacology, Department of Medical Sciences, School of Medicine, University of Castilla-La Mancha (UCLM), 02006 Albacete, SpainTranslational Neuropsychopharmacology Unit, Albacete University Hospital Center, Albacete, SpainNeuropharmacology, Department of Medical Sciences, School of Medicine, University of Castilla-La Mancha (UCLM), 02006 Albacete, SpainNeuropharmacology, Department of Medical Sciences, School of Medicine, University of Castilla-La Mancha (UCLM), 02006 Albacete, SpainInstitute of Molecular Biology and Genetics (IBGM), C/ Sanz y Forés 3, 47003 Valladolid, SpainLaboratory of Bioenergetics, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Umultowska 89, 61-614 Poznan, PolandTranslational Neuropsychopharmacology Unit, Albacete University Hospital Center, Albacete, SpainNeuropharmacology, Department of Medical Sciences, School of Medicine, University of Castilla-La Mancha (UCLM), 02006 Albacete, SpainPreviously, we have shown that SH-SY5Y cells exposed to high concentrations of methadone died due to a necrotic-like cell death mechanism related to delayed calcium deregulation (DCD). In this study, we show that, in terms of their Ca2+ responses to 0.5 mM methadone, SH-SY5Y cells can be pooled into four different groups. In a broad pharmacological survey, the relevance of different Ca2+-related mechanisms on methadone-induced DCD was investigated including extracellular calcium, L-type Ca2+ channels, μ-opioid receptor, mitochondrial inner membrane potential, mitochondrial ATP synthesis, mitochondrial Ca2+/2Na+-exchanger, reactive oxygen species, and mitochondrial permeability transition. Only those compounds targeting mitochondria such as oligomycin, FCCP, CGP 37157, and cyclosporine A were able to amend methadone-induced Ca2+ dyshomeostasis suggesting that methadone induces DCD by modulating the ability of mitochondria to handle Ca2+. Consistently, mitochondria became dramatically shorter and rounder in the presence of methadone. Furthermore, analysis of oxygen uptake by isolated rat liver mitochondria suggested that methadone affected mitochondrial Ca2+ uptake in a respiratory substrate-dependent way. We conclude that methadone causes failure of intracellular Ca2+ homeostasis, and this effect is associated with morphological and functional changes of mitochondria. Likely, this mechanism contributes to degenerative side effects associated with methadone treatment.http://dx.doi.org/10.1155/2012/642482 |
| spellingShingle | Sergio Perez-Alvarez Maria E. Solesio Maria D. Cuenca-Lopez Raquel M. Melero-Fernández de Mera Carlos Villalobos Hanna Kmita Maria F. Galindo Joaquin Jordán Pharmacological Characterization of the Mechanisms Involved in Delayed Calcium Deregulation in SH-SY5Y Cells Challenged with Methadone International Journal of Cell Biology |
| title | Pharmacological Characterization of the Mechanisms Involved in Delayed Calcium Deregulation in SH-SY5Y Cells Challenged with Methadone |
| title_full | Pharmacological Characterization of the Mechanisms Involved in Delayed Calcium Deregulation in SH-SY5Y Cells Challenged with Methadone |
| title_fullStr | Pharmacological Characterization of the Mechanisms Involved in Delayed Calcium Deregulation in SH-SY5Y Cells Challenged with Methadone |
| title_full_unstemmed | Pharmacological Characterization of the Mechanisms Involved in Delayed Calcium Deregulation in SH-SY5Y Cells Challenged with Methadone |
| title_short | Pharmacological Characterization of the Mechanisms Involved in Delayed Calcium Deregulation in SH-SY5Y Cells Challenged with Methadone |
| title_sort | pharmacological characterization of the mechanisms involved in delayed calcium deregulation in sh sy5y cells challenged with methadone |
| url | http://dx.doi.org/10.1155/2012/642482 |
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