Stimulation of histamine H2- (and H1)-receptors activates Ca2+ influx in all-atrans-retinoic acid-differentiated HL-60 cells independently of phospholipase C or adenylyl cyclase

In human neutrophils, histamine H₂-receptors mediate activation of adenylyl cyclase (AC) and inhibition of N-formyl-l-methionyl-l-leucyl-l-phenylalanine (FMLP)-induced superoxide anion (0_inf2^sup–) formation, and in HL-60 promyelocytes, H₂-receptors mediate parallel activation of AC, phospholipase C (PLC) and non-selective cation (NSC) channels. As all-trans-retinoic acid (RA) is successfully used in the differentiation therapy of acute promyelocytic leukaemia, we studied signal transduction in RA-differentiated HL-60 cells. Histamine and the H₂-receptor agonist, impromidine, induced both rises in cAMP levels and cytosolic Ca²⁺ ([Ca²⁺]_i). Substances acting at post-receptor sites to increase cAMP did not increase [Ca²⁺]_i. H₂-but not H₁-receptor antagonists inhibited histamine-induced cAMP accumulation and rises in [Ca²⁺]_i were more effectively inhibited by H₂- than by H₁-receptor antagonists. Histamine-induced rises in [Ca²⁺]_i were completely dependent on the presence of extracellular Ca²⁺ and were abolished by the blocker of NSC channels, Gd³⁺, but were resistant to inhibition by pertussis toxin. Unlike FMLP, histamine did not activate PLC. The effects of FMLP on [Ca²⁺]_i were less sensitive to blockade by Gd³⁺ than those of histamine, and there was no cross-desensitization between the two stimuli. FMLP, but not histamine, inhibited transiently thapsigargin-induced rises in [Ca²⁺]₁. Taken together, our results show that histamine activates AC-mediated cAMP accumulation in RA-differentiated HL-60 cells via H₂-receptors and NSC channel-mediated Ca²⁺ influx via H₂- (and H₁)-receptors. Histamine-induced NSC channel activation is not the consequence of AC- or PLC stimulation and occurs, directly or indirectly, via pertussis toxin-insensitive guanine nucleotide-binding proteins. FMLP and histamine activate Ca²⁺ influx by different mechanisms. There are similarities in H₂-receptor-mediated signal transduction between RA-differentiated HL-60 cells and HL-60 promyelocytes and differences between the former cells and neutrophils, indicating that RA-differentiated HL-60 cells must be considered as partially immature.