The activation of protein kinase C (PKC) either by phorbol esters or through breakdown of phospholipids and generation of the intracellular second messenger diacylglycerol, can modulate the formation of cyclic AMP (cAMP) and cyclic GMP (cGMP) induced by receptor agonists or direct activators of the cyclases. In terms of cAMP, such modulation mediated by PKC, can result in potentiation or inhibition of cAMP formation depending on the cell studied. A correlation was found between cells that express the gamma-isozyme of PKC and cells that exhibit potentiation of cAMP formation in response to PKC activation. NIH 3T3 fibroblasts normally do not express gamma-PKC, and the formation of cAMP is inhibited in response to PKC activation. After transfection with gamma-PKC-containing expression vectors, the fibroblasts now exhibit potentiation of cAMP formation after PKC activation by phorbol esters. PC12 rat pheochromocytoma cells contain a receptor for atrial natriuretic factor (ANF) that upon agonist binding stimulates a particulate guanylate cyclase activity. In addition, a soluble guanylate cyclase is present, which can be activated with compounds such as sodium nitroprusside. Activation of PKC in PC12 cells ether with phorbol esters or through the break-down of phosphoinositides and generation of diacylglycerol, results in inhibition of ANF-mediated, but not nitroprusside-mediated, guanylate cyclase activity. PKC isozyme affect differentially endothelia receptor-mediated activation of phospholipase C in NIH 3T3 fibroblasts. In the presence of gamma-PKC an almost complete inhibition of endothelia-mediated stimulation of phospholipase C is observed, whereas in wild type cells only a slight inhibition (10%) occurs. In gamma-PKC-transfected, but not in wild type NIH 3T3 cells, phosphorylation of phospholipase C (T-isozyme) is observed. Such phosphorylation may explain the down regulation of endothelia -stimulated phosphoinositide breakdown in gamma-PKC transfected cells.
