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CC Chen, J Chang and WC Chen
Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei.
Cultured astrocytes express bradykinin (BK) receptors coupled to phospholipase C (PLC)-mediated phosphoinositide (PI) hydrolysis. Short term (10- or 90-min) treatment of cells with 1 microM 12-O- tetradecanoylphorbol-13-acetate (TPA) decreased BK-induced PI breakdown, but this inhibitory action was lost after 3-hr TPA treatment. Extended (6- or 24-hr) pretreatment resulted in marked potentiation of the BK response. Western blot analysis using protein kinase C (PKC) isozyme-specific antibodies indicated that astrocytes express PKC-alpha, PKC-delta, and PKC-zeta. With TPA treatment of the cells for various times (10 min, 90 min, 3 hr, 6 hr, or 24 hr), translocation of PKC-alpha and PKC-delta from the cytosol to the membrane was seen after 10- or 90-min treatment and restoration to basal levels in the membrane fraction was seen after 3-hr treatment. However, partial or complete down-regulation of PKC-alpha and PKC-delta was seen after 6- or 24-hr treatment, respectively. No translocation or down-regulation of PKC-zeta was seen after either short term or long term TPA treatment. The inactive phorbol ester alpha-TPA had no effect on BK-induced PI hydrolysis or on the translocation or down-regulation of PKC-alpha and PKC-delta. These results suggest that, in unstimulated astrocytes, both PKC-alpha and PKC-delta, but not PKC-zeta, may exert tonic inhibition of BK-mediated PI turnover. After 10- or 90-min TPA treatment, AIF4(-)--but not Ca2+ ionophore-induced PI hydrolysis was inhibited, whereas [3H]BK binding was unaffected, indicating that the site of action of PKC-alpha and PKC-delta in the BK receptor/G protein/PLC pathway is after the receptor and before PLC, i.e., the G protein. After down-regulation of PKC-alpha and -delta, increases in both AIF4(-)-induced inositol phosphate formation and [3H]BK binding contributed to marked potentiation of BK-induced PI responses. Scatchard plot analysis showed an increase in both the maximal number of binding sites and the binding affinity. Both the up-regulation of [3H]BK binding and the subsequent BK-induced PI turnover were blocked by 0.5 microM cycloheximide, a protein synthesis inhibitor. The increase in AIF4(-)-induced PI hydrolysis after 24-hr TPA treatment was also inhibited by cycloheximide, indicating that new synthesis of BK receptors and G proteins was required after down-regulation of PKC- alpha and PKC-delta.(ABSTRACT TRUNCATED AT 400 WORDS)
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