The Journal of Neuroscience, May 1, 2000, 20(9):3129-3138
Plasma Membrane Calcium Pump Isoform 1 Gene Expression Is
Repressed by Corticosterone and Stress in Rat Hippocampus
Aditi
Bhargava1,
Onno
C.
Meijer1, 2,
Mary F.
Dallman2, and
David
Pearce1
1 Division of Nephrology, Department of Medicine, and
Biomedical Sciences Program, and 2 Department of
Physiology, University of California, San Francisco, San Francisco,
California 94143
Glucocorticoids (GCs) are critical to learning and memory, in large
part because of their actions in the hippocampus. Chronic high levels
of GCs have profound effects on hippocampal structure and function and
can even result in irreversible neurodegeneration. Hippocampal GC
actions are mediated by intracellular receptors that modulate the
transcription of specific target genes. In a screen for genes repressed
by GCs in rat hippocampus, we identified plasma membrane calcium pump
isoform 1 (PMCA1), a plasma membrane calcium ATPase. In Northern
blots, PMCA1 was repressed ~33% after a high, but not a low dose of
the GC, corticosterone (B), suggesting glucocorticoid (but not
mineralocorticoid) receptor-mediated repression. Furthermore, in
situ hybridization demonstrated that B significantly downregulated PMCA1 mRNA in all brain regions examined. Repression of
PMCA1 was also observed in cultured hippocampal neurons, but only when
the cells were in the differentiated state. Stress also repressed PMCA1
expression in hippocampus of adrenal-intact animals, and a clear
inverse correlation between B level and PMCA1 mRNA could be discerned.
However, other non-B-dependent factors appeared to be involved in the
response of PMCA1 to stress because, unlike exogenous B, cold stress
did not repress PMCA1 in brain regions other than hippocampus.
Moreover, in the presence of constant B (B-replaced, adrenalectomized
animals), cold stress led to increased hippocampal PMCA1 expression.
These observations suggest that repression of PMCA1 represents one
molecular mechanism by which corticosteroids regulate
Ca2+ homeostasis and hence influence neuronal
activity. Moreover, other stress-related neurohumoral factors appear to
counter the repressive effects of B. Defects in the balance between
GC-mediated and non-GC-mediated effects on PMCA1 expression may have
adverse effects on neuronal function and ultimately result in
irreversible neuronal damage.
Key words:
corticosteroids; hippocampus; target genes; gene
repression; plasma membrane calcium pump; cell-death
Copyright © 2000 Society for Neuroscience 0270-6474/00/2093129-10$05.00/0
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