RT info:eu-repo/semantics/article
T1 Pharmacological characterization of the mechanisms involved in delayed calcium deregulation in SH-SY5Y cells challenged with methadone
A1 Pérez Álvarez, Sergio
A1 Solesio, Maria E.
A1 Cuenca López, María Dolores
A1 Melero Fernández de Mera, Raquel
A1 Villalobos Jorge, Carlos
A1 Kmita, Hanna
A1 Galindo, Maria F.
A1 Jordán, Joaquín
AB 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, -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.
PB Hindawi
SN 1687-8884
YR 2012
FD 2012
LK http://uvadoc.uva.es/handle/10324/45055
UL http://uvadoc.uva.es/handle/10324/45055
LA eng
NO International Journal of Cell Biology, 2012, vol. 2012. 8 p.
NO Producción Científica
DS UVaDOC
RD 23-nov-2024