BIDIRECTIONAL MODULATION OF PARATHYROID HORMONE-RESPONSIVE ADENYLYL-CYCLASE BY PROTEIN-KINASE-C

The temporal pattern with which phorbol 12-myristate 13-acetate (PMA), an activator of protein kinase C (PKC), modulates parathyroid hormone (PTH)-responsive adenylyl cyclase (AC) was evaluated in a clonal oste oblast-like cell line (UMR-106). Brief (less than or equal to 1 h) exp osure of UMR-106 cells to PMA enhanced PTH simulation of AC, whereas m ore prolonged PMA treatment decreased the PTH response, with maximum i nhibition occurring at less than or equal to 6 h. PMA treatment also r esulted in initial activation followed by downregulation of PKC. Expos ure of cells to 1,2-dioctanoyl-sn-glycerol, which activated but did no t downregulate PKC, resulted in bidirectional modulation of PTH-respon sive AC identical to that produced by PMA. Prolonged PMA exposure decr eased PTH receptor number, as determined by radioligand binding studie s, and reduced PTH receptor mRNA levels, assessed by Northern blot ana lysis. Forskolin activation of the catalytic subunit of AC was also de creased after prolonged PMA treatment. The results suggest that activa tion of PKC sequentially stimulates and then inhibits PTH responsivene ss. Inhibition of the PTH response occurs by PKC actions exerted on th e PTH receptor and the AC catalytic subunit.