Pharmacological characterization of the mechanisms involved in delayed calcium deregulation in SH-SY5Y cells challenged with methadone

Sergio Perez-Alvarez, Maria E. Solesio, Maria D. Cuenca-Lopez, Raquel M. Melero-Fernndez De Mera, Carlos Villalobos, Hanna Kmita, Maria F. Galindo, Joaquin Jordán

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3 Scopus citations

Abstract

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 0.5mM 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.

Original languageEnglish (US)
Article number642482
JournalInternational Journal of Cell Biology
DOIs
StatePublished - 2012
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Cell Biology

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