Abstract
We investigated the inter-relationships of superoxide (O 2 - release, membrane depolarization and an increase in cytoplasmic free Ca 2+, [Ca 2+] i, in human granulocytes stimulated by various agonists. When concanavalin A or the Ca 2+ ionophore ionomycin was used as stimulus, an increase in [Ca 2+] i clearly preceded the onset of membrane depolarization, which was followed by O 2 - release. On the other hand, when N-formylmethionylleucylphenylalanine or wheat-germ agglutin was used as stimulus, no demonstrable lag was seen in any of the responses. O 2 release and membrane depolarization stimulated by all these agonists were markedly potentiated in parallel by pretreatment of cells wiht a low concentration of phorbol myristate acetate (0.25 ng/ml), whereas an increase in [Ca 2+] i was not affected or minimally potentiated. The lag time between addition of the stimulus (concanavalin A or ionomycin) and onset of membrane depolarization or O 2 - release was significantly reduced by pretreatment of cells with phorbol myristate acetate, whereas the lag time between addition of concanavalin A and onset of the increase in [Ca 2+] i was not affected. The dose-response curves for triggering of O 2 - release and membrane depolarization by each of receptor-mediated agonists in phorbol myristate acetate-pretreated or control cells were identical. These findings suggest that; (a) an increase in [Ca 2+] i stimulates membrane depolarization indirectly; (b) a low concentration of phorbol myristate acetate potentiates membrane depolarization and O 2 - release by acting primarily at the post-receptor level, in particular, at the level distal to an increase in [Ca 2+] i, but not by augmenting an increase in [Ca 2+] i; and (c) the system provoking membrane depolarization and the system activating NADPH oxidase share a common pathway, which may be susceptible to a low concentration of phorbol myristate acetate.
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