HISTAMINE RECEPTOR-DEPENDENT AND OR RECEPTOR-INDEPENDENT ACTIVATION OF GUANINE-NUCLEOTIDE-BINDING PROTEINS BY HISTAMINE AND 2-SUBSTITUTED HISTAMINE DERIVATIVES IN HUMAN LEUKEMIA (HL-60) AND HUMAN ERYTHROLEUKEMIA (HEL) CELLS/

In dibutyryl cAMP-differentiated human leukemia (HL-60) cells, the pot ent histamine H-1-receptor agonist, 2-(3-chlorophenyl)histamine, activ ates pertussis toxin (PTX)-sensitive guanine nucleotide-binding protei ns (G-proteins) of the G(i)-subfamily by a mechanism which is independ ent of known histamine receptor subtypes (Seifert et al. Mol Pharmacol 45: 578-586, 1994). In order to learn more about this G-protein activ ation, we studied the effects of histamine and various 2-substituted h istamine derivatives in various cell types and on purified G-proteins. In HL-60 cells, histamine and 2-methylhistamine increased cytosolic C a2+ concentration ([Ca2+](i)) in a clemastine-sensitive manner. Phenyl - and thienyl-substituted histamines increased [Ca2+](i) as well, but their effects were not inhibited by histamine receptor antagonists. 2- Substituted histamines activated high-affinity GTPase in HL-60 cell me mbranes in a PTX-sensitive manner, with the lipophilicity of substance s increasing their effectiveness. Although HEL cells do not possess hi stamine receptors mediating rises in [Ca2+](i), 2-(3-bromophenyl)hista mine increased [Ca2+](i) in a PTX-sensitive manner. It also increased GTP hydrolysis by G(i)-proteins in HEL cell membranes. All these stimu latory effects of 2-substituted histamine derivatives were seen at con centrations higher than those required for activation of H-1-receptors . In various other cell types and membrane systems, 2-substituted hist amine derivatives showed no or only weak stimulatory effects on G-prot eins. 2-Substituted histamine derivatives activated GTP hydrolysis by purified bovine brain G(i)/G(0)-proteins and by pure G(i2) (the major PTX-sensitive G-protein in HL-60 and HEL cells). Our data suggest the following: (1) histamine and 2-methylhistamine act as H-1-receptor ago nists in HL-60 cells; (2) incorporation of bulky and lipophilic groups results in loss of H-1-agonistic activity of 2-substituted histamine derivatives in HL-60 cells but causes a receptor independent G-protein -stimulatory activity; (3) the effects of 2-substituted histamine deri vatives on G-proteins are cell-type specific.