Glutamate-induced deregulation of calcium homeostasis and mitochondrial dysfunction in mammalian central neurones

Delayed neuronal death following prolonged (10-15min) stimulation of Glu receptors is known to depend on sustained elevation of cytosolic Ca2+ concentration ([Ca2+](i)) which may persist far beyond the termination of Glu exposure. Mitochondrial depolarization (MD) plays a central role in this Ca2+ deregulation: it inhibits the uniporter-mediated Ca2+ uptake and reverses ATP synthetase which enhances greatly ATP consumption during Glu exposure. MD-induced inhibition of Ca2+ uptake in the face of continued Ca2+ influx through Glu-activated channels leads to a secondary increase of [Ca2+](i) which, in its turn, enhances MD and thus [Ca2+](i). Antioxidants fail to suppress this pathological regenerative process which indicates that reactive oxygen species are not involved in its development. In mature nerve cells ( > 11 DIV), the post-glutamate [Ca2+](i) plateau associated with profound MD usually appears after 10-15 min Glu (100 muM) exposure. In contrast, in young cells ( < 9 DIV) delayed Ca2+ deregulation (DCD) occurs only after 30-60 min Glu exposure. This difference is apparently determined by a dramatic increase in the susceptibility of mitochondia to Ca2+ overload during nerve cells maturation. The exact mechanisms of Glu-induced profound MD and its coupling with the impairment of Ca2+ extrusion following toxic Glu challenge is not clarified yet. Their elucidation demands a study of dynamic changes in local concentrations of ATP, Ca2+, H+, Na+ and protein kinase C using novel methodological approaches. (C) 2003 Elsevier Ltd. All rights reserved.