PROTEIN-KINASE-C ACTIVATION DOWN-REGULATES NATRIURETIC PEPTIDE RECEPTOR-C EXPRESSION VIA TRANSCRIPTIONAL AND POSTTRANSLATIONAL PATHWAYS

Natriuretic peptide receptor C (NPR-C) mRNA expression and ANP-binding activity via NPR-C are significantly down-regulated in HeLa cells wit h phorbol myristate acetate (PMA) treatment. Stabilization of the NPR- C mRNA by PMA indicated that down-regulation of its mRNA was mediated through negative transcriptional regulation, Despite the significant l oss of the mRNA, reduction of NPR-C-specific ANP-binding activity afte r PMA exposure (4 h) was accompanied by a slight decrease in total NPR -C protein (with a 5% loss) and was also produced in the presence of a ctinomycin D or cycloheximide. The inhibitory effect of a long PMA exp osure (18 h) paralleled with a decrease in total NPR-C protein is sugg ested to be dependent on reduction of de novo NPR-C synthesis. PMA-ind uced transcriptional and post-translational dean-regulation of NPR-C w as effectively reversible in the presence of the protein kinase C inhi bitor GF109203X. These findings demonstrate that protein kinase C acti vation downregulated NPR-C expression through transcriptional and post translational pathways and that immediate functional receptor loss was mediated via a post-translational mechanism, such as enhanced recepto r internalization. (C) 1997 Federation of European Biochemical Societi es.