Multiple sites of control of type-1 corticotropin releasing hormone receptor levels in the pituitary.
Hypothalamic corticotropin releasing hormone (CRH) stimulates pituitary ACTH secretion through interaction with type 1 CRH receptors (CRH-R1), the number of which varies during alterations of the hypothalamic-pituitary-adrenal (HPA) axis. CRH-R1 are essential for ACTH responses to stress but CRH receptor content in the pituitary does not correlate with corticotroph responsiveness. This indicates that a small number of receptors is sufficient for full ACTH responses probably through post-receptor interaction with vasopressin (VP) signaling. CRH binding and hybridization studies in adrenalectomized, glucocorticoid-treated or stressed rats revealed divergent levels of CRH receptors and CRH-R1 mRNA in the pituitary, with binding reductions but normal or elevated CRH-R1 mRNA levels during alterations of the HPA axis. Western blot analysis of CRH-R1 protein in pituitary membranes from adrenalectomized rats show unchanged CRH-R1 mRNA levels, but reduced CRH binding associated with significant increases in CRH-R1 protein, suggesting that the decrease in binding is due to homologous desensitization and not to reduced receptor synthesis. In contrast, decreased CRH binding following glucocorticoid administration is associated with reduction in CRH-R1 protein suggesting inhibition of CRH-R1 mRNA translation. Regulation of CRH-R1 translation may involve binding of cytosolic proteins, and a minicistron in the 5'UTR of the CRH-R1 mRNA. Post-transcriptional regulatory mechanisms allowing rapid changes in CRH receptor activity are important for adaptation of corticotroph responsiveness to continuous change in physiological demand.
Nikodemova
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M
Section on Endocrine Physiology, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.
Diehl
C R
CR
Aguilera
G
G
D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D003001:Cloning, Molecular; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D010902:Pituitary Gland / Q000378:metabolism*; D010913:Pituitary-Adrenal System / Q000378:metabolism; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism*; D000099052:CRF Receptor, Type 1
D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1; D000324:Adrenocorticotropic Hormone