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Volume 17, Number 24,
Issue of December 15, 1997
pp. 9554-9564
Measurement of Intracellular Free Zinc in Living Cortical
Neurons: Routes of Entry
Received May 15, 1997; revised Sept. 26, 1997; accepted Sept. 30, 1997.
Stefano L. Sensi,
Lorella M. T. Canzoniero,
Shan Ping Yu,
Howard S. Ying,
Jae-Young Koh,
Geoffrey A. Kerchner, and
Dennis W. Choi
Center for the Study of Nervous System Injury and Department of
Neurology, Washington University School of Medicine, St. Louis,
Missouri 63110
We used the ratioable fluorescent dye mag-fura-5 to measure
intracellular free Zn2+
([Zn2+]i) in cultured
neocortical neurons exposed to neurotoxic concentrations of
Zn2+ in concert with depolarization or glutamate
receptor activation and identified four routes of
Zn2+ entry. Neurons exposed to extracellular
Zn2+ plus high K+ responded with
a peak cell body signal corresponding to a
[Zn2+]i of 35-45 nM. This
increase in [Zn2+]i was attenuated by
concurrent addition of Gd3+, verapamil,
-conotoxin GVIA, or nimodipine, consistent with Zn2+ entry through voltage-gated
Ca2+channels. Furthermore, under conditions favoring
reverse operation of the
Na+-Ca2+ exchanger,
Zn2+ application induced a slow increase in
[Zn2+]i and outward whole-cell current
sensitive to benzamil-amiloride. Thus, a second route of
Zn2+ entry into neurons may be via
transporter-mediated exchange with intracellular
Na+. Both NMDA and kainate also induced rapid
increases in neuronal [Zn2+]i. The
NMDA-induced increase was only partly sensitive to
Gd3+ or to removal of extracellular
Na+, consistent with a third route of entry directly
through NMDA receptor-gated channels. The kainate-induced increase was
highly sensitive to Gd3+ or Na+
removal in most neurons but insensitive in a minority subpopulation ("cobalt-positive cells"), suggesting that a fourth route of
neuronal Zn2+ entry is through the
Ca2+-permeable channels gated by certain subtypes of
AMPA or kainate receptors.
Key words:
mag-fura-5;
voltage-gated calcium channels;
sodium-calcium exchanger;
calcium;
sodium;
glutamate;
AMPA;
NMDA;
neurotoxicity;
global ischemia;
hypoxia
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[Full Text]
|
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|

|
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|
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[Abstract]
[Full Text]
[PDF]
|
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|
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[Abstract]
[Full Text]
[PDF]
|
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|

|
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|
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10246 - 10250.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
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[Abstract]
[Full Text]
[PDF]
|
 |
|

|
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|
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[Abstract]
[Full Text]
[PDF]
|
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|

|
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|
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[Abstract]
[Full Text]
[PDF]
|
 |
|

|
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|
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[Full Text]
[PDF]
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