1 The effects of the specific protein kinase C (PKC) inhibitor, GF109203X, were measured on the cytoplasmic Ca2" concentration ([Ca2+] LaCl3 was inhibited by GF109203X in a concentration-dependent manner (IC50: 3.1+1.1 giM).4 Histamine-induced formation of inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) was not changed in the presence of GF109203X.5 The PKC activating phorbol ester, phorbol 12-myristate 13-acetate (PMA, 1 gM), strongly reduced histamine-induced Ins(1,4,5)P3 formation (58+16%). This effect was reversed by GF109203X (5 giM).Furthermore, PMA diminished histamine evoked Ca2" release (50 + 6%) and blocked Ca2+ entry completely.6 The rise in [Ca2+] caused by blocking endoplasmic reticulum Ca2+-ATPase with thapsigargin (1 jiM), was strongly reduced (57 + 3%) after pretreatment of cells with GF109203X. Downregulation of PKC by long-term pretreatment of cells with PMA (1 gM, 48 h) did not abolish this effect of GF109203X (48 + 3% inhibition). 7 In permeabilized DDT, MF-2 cells preloaded with 45Ca2+ in the presence of GF109203X, the amount of 45Ca2+ released by Ins(1,4,5)P3 (10 jiM) was markedly reduced (42+9%). GF109203X did not release Ca2+ itself and did not impair Ins(1,4,5)P3 receptor function.8 Uptake of 45Ca2+ by intact cells, representing Ca2`entry, was enhanced by GF109203X (65 + 11%), by histamine (24+6%) and also by thapsigargin (121+10%). The GF109203X-and the thapsigargininduced uptake of 45Ca2+ were not additive. 9 These data suggest that GF109203X reduces the filling-state of intracellular Ins(1,4,5)P3 sensitive Ca2+ stores by inhibiting the Ca2+ uptake into these stores, thereby promoting store-dependent (capacitive) Ca2+ entry.