Abstract
Neuronal mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) proteins are glucocorticoid-activated transcription factors that bind identical DNA response elements yet transduce distinct physiological/transcriptional actions. The present study assessed regulation of adrenocorticosteroid receptor RNA and protein following intermittent stress exposure, using Sprague Dawley (S-D) and stress-hyperresponsive Fischer 344 (F344) rat strains. The F344 (but not S-D) strain showed enhanced acute stress responsivity and enhanced corticosterone secretion following prolonged stress. F344 rats also showed reduced responsiveness to a novel stressor after prolonged stress exposure, suggestive of enhanced glucocorticoid negative feed-back. Upon prolonged stress, F344 rats down-regulated MR hnRNA in CA1, CA3, and dentate gyrus. Transcriptional changes were accompanied by decreased expression of the alpha 5' messenger RNA (mRNA) form, consistent with altered promoter utilization. In contrast, alpha 5' splice variant, full-length mRNA, and MR protein expression were not affected by stress in either strain, implying that transcriptional changes do not affect overall mRNA or protein expression. GR protein was increased in pyramidal and granule cell somata/nuclei of F344 rats despite lack of a change in mRNA expression. These data suggest that prolonged stress elicits restricted changes in MR and GR expression in the F344 strain only. Overall, stable expression of adrenocorticosteroid receptors is rigorously defended in hippocampal neurons, apparently through transcriptional and posttranscriptional mechanisms.
Highlights
Chronic stress has inconsistent effects on GR binding, protein expression, and messenger RNA (mRNA) levels (29 –35), suggesting that physiological increases in glucocorticoid secretion may not be sufficient to down-regulate the GR
There was a significant effect of chronic stress on plasma CORT [F(2,43) ϭ 3.40, P Ͻ 0.05], highlighted by a significant increase in stressed Fischer 344 (F344) rats relative to handled and unhandled controls
The relatively circumscribed changes in CORT levels in the stressed Sprague Dawley (S-D) strain should not be interpreted as an ineffective stress regimen, as both strains showed substantial adrenal hypertrophy and thymic atrophy
Summary
Glucocorticoids play a major role in control of GR biosynthesis Both GR mRNA and protein are markedly increased in all hippocampal subfields following adrenalectomy [14, 21,22,23], with the most substantial elevations seen in CA1 [14]. These changes are reversed by low doses of glucocorticoids or aldosterone and can be mimicked by systemic administration of MR antagonists [24], implying MR regulation [25, 26]. Chronic stress has inconsistent effects on GR binding, protein expression, and mRNA levels (29 –35), suggesting that physiological increases in glucocorticoid secretion may not be sufficient to down-regulate the GR
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