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Journal of Neuroscience, Vol 12, 1882-1895, Copyright © 1992 by Society for Neuroscience
Glutamate-induced calcium transient triggers delayed calcium overload and neurotoxicity in rat hippocampal neurons
RD Randall and SA Thayer
Department of Pharmacology, University of Minnesota Medical School, Minneapolis 55455.
Glutamate-induced changes in intracellular free Ca2+ concentration
([Ca2+]i) were recorded in single rat hippocampal neurons grown in primary
culture by employing the Ca2+ indicator indo-1 and a dual- emission
microfluorimeter. The [Ca2+]i was monitored in neurons exposed to 100
microM glutamate for 5 min and for an ensuing 3 hr period. Ninety-two
percent (n = 64) of these neurons buffered the glutamate- induced Ca2+ load
back to basal levels after removal of the agonist; thus, the majority of
cells had not lost the ability to regulate [Ca2+]i at this time. However,
following a variable delay, in 44% (n = 26) of the neurons that buffered
glutamate-induced Ca2+ loads to basal levels, [Ca2+]i rose again to a
sustained plateau and failed to recover. The changes in [Ca2+]i that occur
during glutamate-induced delayed neuronal death can be divided into three
phases: (1) a triggering phase during which the neuron is exposed to
glutamate and the [Ca2+]i increases to micromolar levels, followed by (2) a
latent phase during which the [Ca2+]i recovers to a basal level, and (3) a
final phase that begins with a gradual rise in the [Ca2+]i that reaches a
sustained plateau from which the neuron does not recover. This delayed Ca2+
overload phase correlated significantly with cell death. The same sequence
of events was also observed in recordings from neuronal processes. The
delayed Ca2+ increase and subsequent death were dependent upon the presence
of extracellular Ca2+ during glutamate exposure. Calcium influx during the
triggering phase resulted from the activation of both NMDA and non-NMDA
receptors as indicated by studies using receptor antagonists and ion
substitution. Treatment with TTX (1 microM) or removal of extracellular
Ca2+ for a 30 min window following agonist exposure failed to prevent the
delayed Ca2+ overload. The delayed [Ca2+]i increase could be reversed by
removing extracellular Ca2+, indicating that it resulted from Ca2+ influx.
The three phases defined by changes in the [Ca2+]i during glutamate-induced
neuronal toxicity suggest three distinct targets to which neuroprotective
agents may be directed.
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96(1):
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|
|
|
|
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|
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|
|
|
|
|
|
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81(4):
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|
|
|
|
|
|
|
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96(5):
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[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. A. Connor, S. Razani-Boroujerdi, A. C. Greenwood, R. J. Cormier, J. J. Petrozzino, and R. C. S. Lin
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J Neurophysiol,
January 1, 1999;
81(1):
299 - 306.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. G. Carriedo, H. Z. Yin, S. L. Sensi, and J. H. Weiss
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J. Neurosci.,
October 1, 1998;
18(19):
7727 - 7738.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Tan, Y. Sagara, Y. Liu, P. Maher, and D. Schubert
The Regulation of Reactive Oxygen Species Production during Programmed Cell Death
J. Cell Biol.,
June 15, 1998;
141(6):
1423 - 1432.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. S. Gold, D. B. Reichling, K. F. Hampl, K. Drasner, and J. D. Levine
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J. Pharmacol. Exp. Ther.,
May 1, 1998;
285(2):
413 - 421.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
K. Hyrc, S. D. Handran, S. M. Rothman, and M. P. Goldberg
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J. Neurosci.,
September 1, 1997;
17(17):
6669 - 6677.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Q. X. Chen, K. L. Perkins, D. W. Choi, and R. K. S. Wong
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J. Neurosci.,
June 1, 1997;
17(11):
4032 - 4036.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. R. Grant, B. J. Bacskai, D. E. Pleasure, D. B. Pritchett, M. J. Gallagher, S. J. Kendrick, L. J. Kricka, and D. R. Lynch
N-Methyl-D-aspartate Receptors Expressed in a Nonneuronal Cell Line Mediate Subunit-specific Increases in Free Intracellular Calcium
J. Biol. Chem.,
January 3, 1997;
272(1):
647 - 656.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Sammak, L. Hinman, P. Tran, M. Sjaastad, and T. Machen
How do injured cells communicate with the surviving cell monolayer?
J. Cell Sci.,
January 2, 1997;
110(4):
465 - 475.
[Abstract]
[PDF]
|
|
|
|
|
|
|
T. A. Good and R. M. Murphy
Effect of beta -amyloid block of the fast-inactivating K+ channel on intracellular Ca2+ and excitability in a modeled neuron
PNAS,
December 24, 1996;
93(26):
15130 - 15135.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. F. Schinder, E. C. Olson, N. C. Spitzer, and M. Montal
Mitochondrial Dysfunction Is a Primary Event in Glutamate Neurotoxicity
J. Neurosci.,
October 1, 1996;
16(19):
6125 - 6133.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. J. White and I. J. Reynolds
Mitochondrial Depolarization in Glutamate-Stimulated Neurons: An Early Signal Specific to Excitotoxin Exposure
J. Neurosci.,
September 15, 1996;
16(18):
5688 - 5697.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. M. Lu, H. Z. Yin, J. Chiang, and J. H. Weiss
Ca2+-Permeable AMPA/Kainate and NMDA Channels: High Rate of Ca2+ Influx Underlies Potent Induction of Injury
J. Neurosci.,
September 1, 1996;
16(17):
5457 - 5465.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
O. Meucci and R. J. Miller
gp120-Induced Neurotoxicity in Hippocampal Pyramidal Neuron Cultures: Protective Action of TGF-beta 1
J. Neurosci.,
July 1, 1996;
16(13):
4080 - 4088.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Finkbeiner
Calcium-mediated Gene Expression: Mechanism for Neuronal Plasticity and Survival
Neuroscientist,
November 1, 1995;
1(6):
317 - 320.
[Abstract]
[PDF]
|
|
|
|
|
|
|
J. R. Brorson, C. J. Marcuccilli, and R. J. Miller
Delayed Antagonism of Calpain Reduces Excitotoxicity in Cultured Neurons
Stroke,
July 1, 1995;
26(7):
1259 - 1267.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
A Ghosh and M. Greenberg
Calcium signaling in neurons: molecular mechanisms and cellular consequences
Science,
April 14, 1995;
268(5208):
239 - 247.
[Abstract]
[PDF]
|
|
|
|
|
|
|
S. A. Lipton and P. A. Rosenberg
Excitatory Amino Acids as a Final Common Pathway for Neurologic Disorders
N. Engl. J. Med.,
March 3, 1994;
330(9):
613 - 622.
[Full Text]
|
|
|
|
|
|
|
J Zhang, V. Dawson, T. Dawson, and S. Snyder
Nitric oxide activation of poly(ADP-ribose) synthetase in neurotoxicity
Science,
February 4, 1994;
263(5147):
687 - 689.
[Abstract]
[PDF]
|
|
|
|
|
