TRANS-SYNAPTIC CONTROL OF THE CA2+/PHOSPHOLIPID-DEPENDENT PROTEIN KINASE

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The Ca2+/phospholipid dependent protein kinase (protein kinase C) is an important intracellular mediator of the actions of extracellular signals that stimulate the breakdown of phosphatidylinositol to inositol phosphate and diacylglycerol. Diacylglycerol may be the second messenger, analogous to cAMP, that directly activates protein kinase C. The potential involvement of this enzyme in the functioning of adrenal chromaffin cells and cerebellar granule cells was the subject of this research project. Protein kinase C is present in bovine adrenal medulla and its constituent chromaffin cells in significant amounts compared to other tissue. In membranes and cytosol of the medulla, there are several specific endogenous substrate proteins for the enzyme. Treatment of primary cultures of chromaffin cells with phorbol esters, drugs which can substitute for diacylglycerol in the in vitro and in vivo activation of the enzyme, induce an apparent translocation of soluble enzyme activity to a membrane associated form. This translocation is specific for those phorbol esters that can activate the enzyme in vitro. Concomitant with the translocation of the enzyme activity is a significant phorbol ester induced release of catecholamines. Receptor-dependent activation of protein kinase C in cerebellar granule cells is also under study. Preliminary results indicate that glutamate, which stimulates phosphatidylinositol turnover in these cells, causes an approximate 20 to 30% increase in membrane-associated enzyme activity. The above studies indicate a potential prominent role for protein kinase C in chromaffin cells and cerebellar granule cells and that the receptor dependent activation of the enzyme may be manifested as a translocation of enzyme activity from cytosol to membrane.