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Regulation of Corticotropin‐Releasing Factor Receptor Function in Human Y‐79 Retinoblastoma Cells: Rapid and Reversible Homologous Desensitization but Prolonged Recovery

Abstract: 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.