Histamine modulation of Ca2+ homeostasis in human neutrophils

The influence of histamine on the basal intracellular free Ca2+ concentration ([Ca2+]i) and agonist-induced increases of [Ca2+]i was studied in Fura-2-loaded neutrophils. Histamine was unable to change the basal [Ca2+]i at concentrations (10(-6)-10(-4) M) that have been shown to cause a rapid increase in [Ca2+]i in a variety of cell types. Histamine, in contrast, was found to inhibit dose-dependently the rise in [Ca2+]i induced by two neutrophil receptor agonists, N-formylmethionyl-leucylphenylalanine (fMLP) and serum-opsonized zymosan particles. The histamine inhibition was shown to be specific for H2 receptor activation by blocking experiments with selective H1 and H2 receptor antagonists. In the absence of extracellular Ca2+, histamine failed to inhibit the agonist-induced rise in [Ca2+]i, indicating that histamine does not affect the release of Ca2+ from internal pools. Forskolin, which mimics the biochemical effects of H2 receptor activation by directly stimulating adenylate cyclase, also decreased the Ca2+ transients induced by receptor agonists. Similarly, 3-isobutyl-1-methylxanthine (IBMX), a phosphodiesterase inhibitor, reduced the Ca2+ response of activated neutrophils. These data suggest that in human neutrophils (1) no functional H1 receptors are present or alternatively H1 receptors are not coupled to cellular Ca2+ metabolism, and (2) H2 receptors modulate the receptor-triggered Ca2+ flux via the cAMP second messenger system.