The effects of hepatocyte growth factor (HGF) on intracellular CaL+ mobilization were studied using fura-2-loaded single rat hepatocytes. Hepatocytes microperfused with different amounts of HGF responded with a rapid concentration-dependent rise in the cytosolic free Ca2+ concentration with a maximum increase of 142% at 80 ng/ml of HCF. The lag period of the Ca" response was decreased with increasing HGF concentrations, being 64 2 12 s, 42 i 6 s, and 14 5 2 s, respectively, with 8, 20, and 80 ngiml of HGF. The detailcd pattern of Ca2+ transients, however, was variable. Out of 16 cells tested using 20 ng/ml ot t iGF, 68% showed sustained oscillatory responses, whereas other cells showed a sustained increase in the cytosolic-frce Ca2 ' upon expowre to HGF, which was dependent on the presence of extracellular Caz+. HCF also induced CaL+ entry across the plasma membrane. Mobilization of Ca'+ by H L F was accompanied by a rapid accumulation of inositol 1,4,5-trisphosphate (Ins 1,4,5-P,). The effects of HGF and epidermal growth factor (EGF) were comparable and partly additive for Ins 1,4,5-P, production and for the sustained phase of Ca" mobilization. Preincubation of cells with 10 pM of genistein to inhibit protein tyrosine kinases abolished thc HCF-induced Ca2 '~ response and also inhibited HGF-induced Ins 1,4,5-P, production in rat liver cells. These data indicate that early events in the 5ignal transduction pathways mediated by HGF and EGF have in common the requirements for tyrosine kinase activity, Ins 1,4,5-P, production, and CaL+ mobilization.