Glutamate-induced deregulation of calcium homeostasis and mitochondrial dysfunction in mammalian central neurones.
Delayed neuronal death following prolonged (10-15 min) stimulation of Glu receptors is known to depend on sustained elevation of cytosolic Ca(2+) concentration ([Ca(2+)](i)) which may persist far beyond the termination of Glu exposure. Mitochondrial depolarization (MD) plays a central role in this Ca(2+) deregulation: it inhibits the uniporter-mediated Ca(2+) uptake and reverses ATP synthetase which enhances greatly ATP consumption during Glu exposure. MD-induced inhibition of Ca(2+) uptake in the face of continued Ca(2+) influx through Glu-activated channels leads to a secondary increase of [Ca(2+)](i) which, in its turn, enhances MD and thus [Ca(2+)](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 [Ca(2+)](i) plateau associated with profound MD usually appears after 10-15 min Glu (100 microM) exposure. In contrast, in young cells (<9 DIV) delayed Ca(2+) 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 Ca(2+) overload during nerve cells maturation. The exact mechanisms of Glu-induced profound MD and its coupling with the impairment of Ca(2+) extrusion following toxic Glu challenge is not clarified yet. Their elucidation demands a study of dynamic changes in local concentrations of ATP, Ca(2+), H(+), Na(+) and protein kinase C using novel methodological approaches.
Khodorov
Boris
B
Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, Baltiiskaya Str. 8, 125315 Moscow, Russia. boriskhodorov@mtu-net.ru
D000818:Animals; D002118:Calcium / Q000502:physiology*; D018698:Glutamic Acid / Q000494:pharmacology / Q000502:physiology*; D006706:Homeostasis; D006801:Humans; D008322:Mammals; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D008954:Models, Biological; D009474:Neurons / Q000502:physiology*
D018698:Glutamic Acid; D002118:Calcium