STAUROSPORINE INHIBITS INOSITOL PHOSPHATE FORMATION IN BOVINE ADRENAL-MEDULLARY CELLS

The effect of protein kinase C activators and inhibitors on histamine- stimulated phospholipase C in bovine adrenal medullary cells has been investigated. The protein kinase C activators, phorbol 12,13-dibutyrat e (PDB) or sn-1,2-dioctanoylglycerol (DOG), inhibited histamine-stimul ation of phospholipase C. This inhibition was prevented by the protein kinase C-selective inhibitor Ro 31-8220 (3-{1-[3-(2-isothioureido) 3- yl}-4-(1-methylindol-3-yl)-3-pyrrolin-2,5-dione) but not the broad spe ctrum protein kinase inhibitor staurosporine. Indeed staurosporine on its own inhibited both the histamine-stimulated response and, in perme abilized cells, phospholipase C activated by Ca2+. Staurosporine inhib ition of phospholipase C is unlikely to be mediated via protein kinase A or Ca2+/calmodulin-dependent protein kinase because it was not repr oduced by selective inhibition of these kinases. Staurosporine treatme nt, however, reduced inositol phospholipid levels in stimulated cells. Thus staurosporine and Ro 31-8220, two widely used protein kinase C i nhibitors, have quite different effects on phospholipase C activation. Furthermore, staurosporine may cause this inhibition through a reduct ion in the level of phospholipase C substrate.