The role of Ca 2 + influx in activating phospholipase C in bovine adrenal chromaffin cells has been investigated. Phospholipase C activity in response to K + depolarization (56 mM) was blocked by the L-type Ca 2 + channel antagonist nifedipine and partially inhibited by the ω-conotoxins GVIA and MVIIC. In contrast, phospholipase C activity in response to histamine receptor activation was unaffected by ω-conotoxin GVIA and partially inhibited by ω-conotoxin MVIIC or nifedipine. This response was however markedly inhibited by the non-selective Ca 2 + channel antagonists La 3 + or 1-[β-[3-(4-Methoxyphenyl)propoxy]-4-methoyphenethyl]-H-imidazole (SKF-96365). Despite this Ca 2 + dependence phospholipase C activity was not increased during periods of ''capacitative'' Ca 2 + inflow generated by histamine-, caffeine- or thapsigargin-mediated depletion of internal Ca 2 + stores. Thus, while Ca 2 + influx in response to K + depolarization or G-protein receptor activation can increase phospholipase C activity in these cells, in the latter case it appears to be ineffective unless there is concurrent agonist occupation of the receptor.