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NEUROPHARMACOLOGY

Mediation of Corticotropin Releasing Factor Type 1 Receptor Phosphorylation and Desensitization by Protein Kinase C: A Possible Role in Stress Adaptation

Department of Veterans Affairs Healthcare System and Department of Psychiatry, University of California, San Diego, La Jolla, California

Protein kinase C (PKC)-mediated desensitization of the corticotropin releasing factor type 1 (CRF₁) receptor was investigated in human retinoblastoma Y79 and transfected COS-7 cells. Because stimulation of Y79 cells with CRF resulted in large (30-fold) increases in intracellular cAMP accumulation without changing inositol phosphate levels, the CRF₁ receptor expressed in retinoblastoma cells couples to G_s, but not to G_q, and predominantly signals via the protein kinase A cascade. Direct activation of PKC by treatment with the phorbol ester phorbol 12-myristate 13-acetate (PMA) or 1,2-dioctanoyl-sn-glycerol (DOG) desensitized CRF₁ receptors in Y79 cells, reducing the maximum for CRF- (but not forskolin)-stimulated cAMP accumulation by 56.3 ± 1.2% and 40.4 ± 2.1%, respectively (p < 0.001). Pretreating Y79 cells with the PKC inhibitor bisindolylmaleimide I (BIM) markedly inhibited PMA's desensitizing action on CRF-stimulated cAMP accumulation, but did not affect homologous CRF₁ receptor desensitization. Retinoblastoma cells were found to express PKC, I, II, , , and RACK1. When and isoforms of PKC were down-regulated 80 to 90% by a 48-h PMA exposure, PMA-induced CRF₁ receptor desensitization was abolished. In transfected COS-7 cells the magnitude of CRF₁ receptor phosphorylation after a 5-min exposure to PMA was 2.32 ± 0.21-fold greater compared with the basal level. Pretreating COS-7 cells with BIM abolished PMA-induced CRF₁ receptor phosphorylation. These studies demonstrate that protein kinase C (possibly and isoforms) has an important role in the phosphorylation and heterologous desensitization of the CRF₁ receptor.

Address correspondence to: Dr. Richard L. Hauger, VA Healthcare System and Department of Psychiatry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0603. E-mail: rhauger{at}ucsd.edu

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