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Volume 16, Number 17,
Issue of September 1, 1996
pp. 5457-5465
Copyright ©1996 Society for Neuroscience
Ca2+-Permeable AMPA/Kainate and NMDA Channels: High
Rate of Ca2+ Influx Underlies Potent Induction of
Injury
Received May 6, 1996; revised June 13, 1996; accepted June 18, 1996.
You Ming Lu1,
Hong Zhen Yin1,
Juna Chiang1, and
John H. Weiss1, 2, 3
Departments of 1 Neurology, 2 Anatomy and
Neurobiology, and 3 Psychobiology, University of
California, Irvine, Irvine, California 92717-4290
Neurodegeneration may occur secondary to glutamate-triggered
Ca2+ influx through any of three routes: NMDA channels,
voltage-sensitive Ca2+ channels (VSCC), and
Ca2+-permeable AMPA/kainate channels (Ca-A/K). This study
aims to examine Ca2+ ion dynamics in the generation of
excitotoxic injury by correlating the relative amounts of
45Ca2+ that flow into cortical neurons through
each of these routes over a 10 min epoch (``10 min Ca2+
loads;'' a measure of influx rate), with resultant levels of
intracellular free Ca2+ ([Ca2+]i)
and subsequent injury. Neurons possessing Ca-A/K make up a small subset
(~13%) of cortical neurons in culture, which can be identified by a
histochemical stain based on kainate-stimulated Co2+ uptake
(Co2+(+) neurons) and which are unusually vulnerable to
AMPA/kainate receptor-mediated injury. Initial studies using brief
kainate exposures (to selectively destroy Co2+(+) neurons)
along with kainate-triggered 45Ca2+ influx
measurements suggested that kainate causes rapid Ca2+
influx into Co2+(+) neurons (comparable to that caused by
NMDA). Influx through both Ca-A/K and NMDA channels increased
proportionately with extracellular Ca2+, suggesting that
these channels have high Ca2+ permeability.
When cultures were subjected to exposures that gave similar 10 min
Ca2+ loads through different routes, comparable levels of
injury were observed, suggesting that net intracellular
Ca2+ accumulation is a critical determinant of injury.
However, the relationship between [Ca2+]i and
influx was less direct: although exposures that gave the lowest or
highest 10 min Ca2+ loads showed correspondingly lower or
higher mean [Ca2+]i responses, there appears
to be a wide range of exposures over which individual neuronal
differences and sequestration/buffering mechanisms obscure
[Ca2+]i as a reflection of influx rate.
Key words:
calcium;
neurotoxicity;
excitotoxicity;
glutamate;
Fura-2;
neuron
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