Mechanisms of destabilization of Ca2+-homeostasis of brain neurons caused by toxic glutamate challenge.
The long-term stimulation of mammalian central neurons with an excitatory neuromediator, glutamate, results in destabilization of Ca2+-homeostasis caused mainly by an impairment of the systems of excessive Ca2+ extrusion from the cytoplasm both into the environment (Na+/Ca2+-exchanger, Ca2+/H+ pump) and mitochondria. The data available suggest that inhibition of the mitochondrial Ca2+ uptake following the glutamate action is due to the strong depolarization of inner mitochondrial membrane caused by opening of the "large pore" in response to the Ca2+ overload and overproduction of free oxygen radicals and NO. The mechanism of deterioration of Ca2+ extrusion from the neuron into extracellular medium following the glutamate challenge has not been yet fully clarified. It is only known that some factors inhibiting or irreversibly altering the functions of Na+/Ca2+-exchanger and Ca2+/H+ pump are accumulated in the cell during the prolonged action of glutamate. They include lowering of ATP concentration and pHi, as well as overproduction of free oxygen radicals and products of lipid peroxidation. The exact contribution of these factors to the final destabilization of Ca2+ homeostasis is under study. A good correlation between the glutamate-induced mitochondrial depolarization and the failure of neurons to extrude excessive Ca2+ from the cytoplasm during the post-glutamate period indicates that at this period the mitochondrial dysfunction is critical for the destabilization of Ca2+ homeostasis.
Khodorov
B I
BI
Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, Moscow. rans.khodorov@g23.relcom.ru
D000818:Animals; D001921:Brain / Q000166:cytology / Q000502:physiology*; D002118:Calcium / Q000502:physiology*; D018698:Glutamic Acid / Q000494:pharmacology / Q000502:physiology*; D006706:Homeostasis; D006801:Humans; D009474:Neurons / Q000502:physiology*
D018698:Glutamic Acid; D002118:Calcium