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

https://doi.org/10.1016/j.pbiomolbio.2003.10.002Get rights and content
Under an Elsevier user license
open archive

Abstract

Delayed neuronal death following prolonged (10–15 min) 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 μM) 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.

Abbreviations

CGC, cerebellar granule cells
Δψm, mitochondrial membrane potential
MD, mitochondrial depolarization
[Ca2+]i, cytosolic calcium concentration
[Ca2+]m, mitochondrial calcium concentration
[Na+]i, cytosolic sodium concentration
pHi, cytosolic pHi
PKC, protein kinase c
PMCA, plasma membrane Ca2+-ATPase
enEAA, endogenous excitatory amino acids
Glu, glutamate
NMDA, N-methyl-d-aspartate
MK-801, (+)5-methyl-10-11-dihydro-5N-dibenzocyclohepten-5,10-imine
APV, 2-amino-5-phosphonovalerate
CNQX, 6-cyano-7-nitroquinoxaline-2,3-dione, Rh123, rhodamine 123
2DG, 2-deoxy-d-glucose
EGTA, ethylen glycol bis(aminoethylether)tetra-accetate
CCCP, carbonyl m-chlorophenylhydrazone
FCCP, carbonyl cyanide p-trifluoromethoxyphenil hydrazone
EU, exchanger units

Cited by (0)