Studies with the calcium ionophore, A23187, and the phorbol ester, TPA, in RBL-2H3 cells indicate that increases in cytosolic calcium concentrations or activation of kinase C alone is an inadequate stimulatory signal for histamine release. A combination of the signals provide a stimulus for release. Exposure of cells, for example, to low concentrations of A23187 and TPA, which by themselves do not stimulate release, can induce near maximal histamine secretion. However, activation of kinase C may serve both to promote secretion and to inhibit initial stimulatory signals. In antigen stimulated cells, TPA at 5-50 nM concentrations markedly suppresses phosphoinositide breakdown and increases cytosolic calcium concentrations in a concentration-dependent fashion. Later stages of the secretory process appear to rely on Ca2+-calmodulin dependent steps. Calmodulin inhibitors at pharmacologically relevant concentrations inhibit histamine release. Inhibition of phosphoinositide breakdown is observed with some of these inhibitors but only at high concentrations of drug (50-100 nM).
