Modulation of responsiveness to cAMP stimulating agonists by phorbol ester in fetal rat osteoblasts

We studied the effect of activation of protein kinase C (PKC) by a phorbol ester on cAMP accumulation in fetal rat osteoblasts. Activation of PKC by phorbol 12‐myristate 13‐acetate (PMA) caused a potentiation of cAMP accumulation induced by parathyroid hormone (PTH), forskolin, and cholera toxin. The results suggest that the potentiating effect of PMA on PTH‐induced cAMP accumulation was not due to an effect on the PTH‐receptor nor to an effect on cAMP degradation, as the effect of PMA persisted in the presence of a phosphodiesterase inhibitor. Pretreatment of the cells with pertussis toxin did not prevent the action of PMA, indicating that PMA does not act via the inhibitory G‐protein. PMA had a biphasic effect on prostaglandin E2 (PGE2)‐induced cAMP accumulation; i.e., at concentrations ⩾ 10−6 M, PMA potentiated the PGE2‐induced cAMP response but PMA attenuated cAMP accumulation induced by concentrations of PGE2 ⩽ 5.10−7 M. From our data we conclude that PKC can interact with a stimulated cAMP pathway in a stimulatory and inhibitory manner. Potentiation of cAMP accumulation is probably due to modification of the adenylate cyclase complex, whereas attenuation of stimulated cAMP accumulation appears to be due to an effect on a different site of the cAMP generating pathway, which may be specific to PGE2‐induced cAMP accumulation.

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