PMID- 10457062
OWN - NLM
STAT- MEDLINE
DCOM- 19991122
LR  - 20190513
IS  - 0022-3751 (Print)
IS  - 1469-7793 (Electronic)
IS  - 0022-3751 (Linking)
VI  - 519 Pt 2
IP  - Pt 2
DP  - 1999 Sep 1
TI  - Glutamate-induced mitochondrial depolarisation and perturbation of calcium 
      homeostasis in cultured rat hippocampal neurones.
PG  - 451-66
AB  - 1. The objective of this study was to clarify the relationships between loss of 
      mitochondrial potential and the perturbation of neuronal Ca2+ homeostasis induced 
      by a toxic glutamate challenge. Digital fluorescence imaging techniques were 
      employed to monitor simultaneously changes in cytoplasmic Ca2+ concentration 
      ([Ca2+]i) and mitochondrial potential (DeltaPsim) in individual hippocampal 
      neurones in culture coloaded with fura-2 AM or fura-2FF AM and rhodamine 123 (Rh 
      123). 2. In most cells (96 %) at 6-7 days in vitro (DIV) and in a small 
      proportion of cells (29 %) at 11-17 DIV the [Ca2+]i increase induced by exposure 
      to 100 microM glutamate for 10 min was associated with a small mitochondrial 
      depolarisation, followed by mitochondrial repolarisation, and a degree of 
      recovery of [Ca2+]i following glutamate washout. In the majority of neurones at 
      11-17 DIV (71 %), exposure to glutamate for 10 min induced a profound mono- or 
      biphasic mitochondrial depolarisation, which was clearly correlated with a 
      sustained [Ca2+]i plateau despite the removal of glutamate. 3. Addition of 
      glutamate receptor antagonists (15 microM MK-801 plus 75 microM 
      6-cyano-7-nitroquinoxaline-2, 3-dione (CNQX)) to the washout solution did not 
      affect the post-glutamate [Ca2+]i plateau in neurones exhibiting a profound 
      mitochondrial depolarisation but greatly improved [Ca2+]i recovery in those 
      neurones undergoing only a small mitochondrial depolarisation, suggesting that 
      the release of endogenous glutamate delays [Ca2+]i recovery in the postglutamate 
      period. 4. Cyclosporin A (500 nM) or N-methyl Val-4-cyclosporin A (200 nM) 
      delayed or even prevented the development of the second phase of mitochondrial 
      depolarisation in cells at 11-17 DIV and increased the proportion of neurones 
      exhibiting a small monophasic mitochondrial depolarisation and [Ca2+]i recovery 
      upon glutamate removal. 5. We have thus described a striking correlation between 
      mitochondrial depolarisation and the failure of cells to restore [Ca2+]i 
      following a toxic glutamate challenge. These data suggest that mitochondrial 
      dysfunction plays a major role in the deregulation of [Ca2+]i associated with 
      glutamate toxicity.
FAU - Vergun, O
AU  - Vergun O
AD  - Department of Physiology, University College London, Gower Street, London WC1E 
      6BT, UK. o.vergun@ucl.ac.uk
FAU - Keelan, J
AU  - Keelan J
FAU - Khodorov, B I
AU  - Khodorov BI
FAU - Duchen, M R
AU  - Duchen MR
LA  - eng
GR  - Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - J Physiol
JT  - The Journal of physiology
JID - 0266262
RN  - 1KSV9V4Y4I (Cesium)
RN  - 3KX376GY7L (Glutamic Acid)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Adenosine Triphosphate/physiology
MH  - Animals
MH  - Calcium/*physiology
MH  - Cells, Cultured
MH  - Cesium/pharmacology
MH  - Electrophysiology
MH  - Glutamic Acid/*toxicity
MH  - Hippocampus/cytology/drug effects/*physiology
MH  - Homeostasis/*drug effects
MH  - Image Processing, Computer-Assisted
MH  - Kinetics
MH  - Mitochondria/drug effects/*physiology
MH  - Neurons/drug effects/*physiology
MH  - Rats
PMC - PMC2269520
EDAT- 1999/08/24 00:00
MHDA- 1999/08/24 00:01
PMCR- 2000/09/01
CRDT- 1999/08/24 00:00
PHST- 1999/08/24 00:00 [pubmed]
PHST- 1999/08/24 00:01 [medline]
PHST- 1999/08/24 00:00 [entrez]
PHST- 2000/09/01 00:00 [pmc-release]
AID - PHY_9345 [pii]
AID - 10.1111/j.1469-7793.1999.0451m.x [doi]
PST - ppublish
SO  - J Physiol. 1999 Sep 1;519 Pt 2(Pt 2):451-66. doi: 
      10.1111/j.1469-7793.1999.0451m.x.