Mathematical modeling of delayed calcium deregulation in brain neurons caused by hyperstimulation of glutamate receptors

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.

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Inhibition of glutamate-induced delayed calcium deregulation by 2-APB and La3+ in cultured cortical neurones

Journal of Neurochemistry ◽

10.1111/j.1471-4159.2004.02732.x ◽

2004 ◽

Vol 91 (2) ◽

pp. 471-483 ◽

Cited By ~ 32

Author(s):

Christos Chinopoulos ◽

Akos A. Gerencser ◽

Judit Doczi ◽

Gary Fiskum ◽

Vera Adam-Vizi

Keyword(s):

Calcium Deregulation ◽

Delayed Calcium Deregulation

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Characterizing calcium influx via voltage- and ligand-gated calcium channels in embryonic Alligator neurons in culture

Translational Neuroscience ◽

10.2478/s13380-013-0132-3 ◽

2013 ◽

Vol 4 (3) ◽

Author(s):

Weina Ju ◽

Jiang Wu ◽

Michael Pritz ◽

Rajesh Khanna

Keyword(s):

Calcium Channels ◽

Calcium Influx ◽

Present Report ◽

Initial Step ◽

Nmda Receptor Antagonist ◽

Brain Neurons ◽

Calcium Deregulation ◽

Voltage Gated Calcium Channels ◽

Physiological Properties ◽

Artificial Cerebrospinal Fluid

AbstractVertebrate brains share many features in common. Early in development, both the hindbrain and diencephalon are built similarly. Only later in time do differences in morphology occur. Factors that could potentially influence such changes include certain physiological properties of neurons. As an initial step to investigate this problem, embryonic Alligator brain neurons were cultured and calcium responses were characterized. The present report is the first to document culture of Alligator brain neurons in artificial cerebrospinal fluid (ACSF) as well as in standard mammalian tissue culture medium supplemented with growth factors. Alligator brain neuron cultures were viable for at least 1 week with unipolar neurites emerging by 24 hours. Employing Fura-2 AM, robust depolarizationinduced calcium influx, was observed in these neurons. Using selective blockers of the voltage-gated calcium channels, the contributions of N-, P/Q-, R-, T-, and L-type channels in these neurons were assessed and their presence documented. Lastly, Alligator brain neurons were challenged with an excitotoxic stimulus (glutamate + glycine) where delayed calcium deregulation could be prevented by a classical NMDA receptor antagonist.

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