INHIBITORS OF PROTEIN KINASE-C PROLONG THE FALLING PHASE OF EACH FREE-CALCIUM TRANSIENT IN A HORMONE-STIMULATED HEPATOCYTE

Many cells generate oscillations in cytoplasmic free Ca2+ concentration ('free Ca') when stimulated with Ca-mobilizing hormones. The frequency of repetitive free-Ca transients in a rat hepatocyte is a function of hormone concentration and can be depressed by phorbol esters. We show here that the protein kinase C (PKC) inhibitors staurosporine and shingosine can reverse the effects of phorbol dibutyrate on the frequency of free-Ca transients induced by phenylephrine or vasopressin. An important feature of the hepatocyte free-Ca oscillator is that the transient's time course, particularly the rate of fall of free Ca from peak to resting, depends on the species of agonist, and is measurably different for phenylephrine, vasopressin, angiotensin II or ATP. We show here that the rate of fall of free Ca in transients induced by phenylephrine or vasopressin is markedly decreased after treatment of the cells with a PKC inhibitor. A receptor-controlled oscillator model is discussed, in which PKC provides negative feedback during the falling phase of free-Ca transients.