Regulation of corticotropin-releasing factor receptor function in human Y-79 retinoblastoma cells: rapid and reversible homologous desensitization but prolonged recovery.
Homologous receptor desensitization is an important regulatory response to continuous activation by agonist that involves the uncoupling of a receptor from its G protein. When human retinoblastoma Y-79 cells expressing corticotropin-releasing factor (CRF) receptors were preincubated with CRF for 10 min-4 h, a time-dependent reduction in both the peak and sensitivity of CRF-stimulated intracellular cyclic AMP (cAMP) accumulation developed with a t1/2 of 38 min and an EC50 of 6-7 nM CRF. CRF receptor desensitization was slowly reversible after a 4-h CRF preincubation with a t1/2 of 13 h and a full restoration of cAMP responsiveness to CRF at 24 h following the removal of 10 nM CRF. Because the ability of vasoactive intestinal peptide, forskolin, or (-)-isoproterenol to stimulate cAMP accumulation was not diminished in Y-79 cells desensitized with 10 nM CRF, the observed desensitization was considered to be a specific homologous action of CRF. CRF receptor desensitization was markedly attenuated by CRF receptor antagonists, which alone did not produce any appreciable reduction in CRF-stimulated cAMP accumulation. Although recent reports have demonstrated a rapid decline in steady-state levels of CRF receptor type 1 (CRF-R1) mRNA in anterior pituitary cells during several hours of exposure to CRF, there was no observed reduction in CRF-R1 mRNA levels when Y-79 cells were preincubated with 10 nM CRF for 10 min-24 h despite a rapid time- and concentration-dependent loss of CRF receptors from the retinoblastoma cell surface.
Hauger
R L
RL
Department of Molecular Neuroendocrinology, Max Planck Institute for Experimental Medicine, Goettingen, Germany.
Dautzenberg
F M
FM
Flaccus
A
A
Liepold
T
T
Spiess
J
J
D000262:Adenylyl Cyclases / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D015152:Blotting, Northern; D005576:Colforsin / Q000494:pharmacology; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D008565:Membrane Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018019:Receptors, Corticotropin-Releasing Hormone / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics*; D012175:Retinoblastoma; D012680:Sensitivity and Specificity; D013997:Time Factors; D014407:Tumor Cells, Cultured / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology
D000318:Adrenergic beta-Agonists; D008565:Membrane Proteins; D012333:RNA, Messenger; D018019:Receptors, Corticotropin-Releasing Hormone; D005576:Colforsin; D014660:Vasoactive Intestinal Peptide; D003346:Corticotropin-Releasing Hormone; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D007545:Isoproterenol