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The Journal of Neuroscience, August 15, 2001, 21(16):6069-6076
The Activation of Dopamine D4 Receptors Inhibits Oxidative
Stress-Induced Nerve Cell Death
Kumiko
Ishige,
Qi
Chen,
Yutaka
Sagara, and
David
Schubert
Cellular Neurobiology Laboratory, The Salk Institute for Biological
Studies, La Jolla, California 92037
Oxidative stress is thought to be the cause of nerve cell death in
many CNS pathologies, including ischemia, trauma, and neurodegenerative disease. Glutamate kills nerve cells that lack ionotropic glutamate receptors via the inhibition of the cystine-glutamate antiporter x , resulting in the inhibition of cystine uptake,
the loss of glutathione, and the initiation of an oxidative
stress cell death pathway. A number of catecholamines were found to
block this pathway. Specifically, dopamine and related ligands inhibit
glutamate-induced cell death in both clonal nerve cell lines and rat
cortical neurons. The protective effects of dopamine, apomorphine, and
apocodeine, but not epinephrine and norepinephrine, are antagonized by
dopamine D4 antagonists. A dopamine D4 agonist also protects, and this
protective effect is inhibited by U101958, a dopamine D4 antagonist.
Although the protective effects of some of the catecholamines are
correlated with their antioxidant activities, there is no correlation
between the protective and antioxidant activities of several other
ligands. Normally, glutamate causes an increase in reactive oxygen
species (ROS) and intracellular Ca2+. Apomorphine
partially inhibits glutamate-induced ROS production and blocks the
opening of cGMP-operated Ca2+ channels that lead to
Ca2+ elevation in the late part of the cell death
pathway. These data suggest that the protective effects of apomorphine
on oxidative stress-induced cell death are, at least in part, mediated
by dopamine D4 receptors via the regulation of cGMP-operated
Ca2+ channels.
Key words:
HT22 cells; cell death; apomorphine; apocodeine; dopamine
D4 receptors; glutamate; cGMP
Copyright © 2001 Society for Neuroscience 0270-6474/01/21166069-08$05.00/0
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