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

被引:23
作者
HAGELUKEN, A
GRUNBAUM, L
KLINKER, JF
NURNBERG, B
HARHAMMER, R
SCHULTZ, G
LESCHKE, C
SCHUNACK, W
SEIFERT, R
机构
[1] FREE UNIV BERLIN, INST PHARMAKOL, W-1000 BERLIN, GERMANY
[2] FREE UNIV BERLIN, INST PHARM, D-14195 BERLIN, GERMANY
关键词
CYTOSOLIC CA2+ CONCENTRATION; G-PROTEINS; GTPASE; HISTAMINE H-1-RECEPTOR; HUMAN MYELOID CELLS; PERTUSSIS TOXIN; 2-SUBSTITUTED HISTAMINE DERIVATIVES;
D O I
10.1016/0006-2952(94)00514-M
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
In dibutyryl cAMP-differentiated human leukemia (HL-60) cells, the potent histamine H-1-receptor agonist, 2-(3-chlorophenyl)histamine, activates pertussis toxin (PTX)-sensitive guanine nucleotide-binding proteins (G-proteins) of the G(i)-subfamily by a mechanism which is independent of known histamine receptor subtypes (Seifert et al. Mol Pharmacol 45: 578-586, 1994). In order to learn more about this G-protein activation, we studied the effects of histamine and various 2-substituted histamine derivatives in various cell types and on purified G-proteins. In HL-60 cells, histamine and 2-methylhistamine increased cytosolic Ca2+ 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 membranes in a PTX-sensitive manner, with the lipophilicity of substances increasing their effectiveness. Although HEL cells do not possess histamine receptors mediating rises in [Ca2+](i), 2-(3-bromophenyl)histamine increased [Ca2+](i) in a PTX-sensitive manner. It also increased GTP hydrolysis by G(i)-proteins in HEL cell membranes. All these stimulatory effects of 2-substituted histamine derivatives were seen at concentrations higher than those required for activation of H-1-receptors. In various other cell types and membrane systems, 2-substituted histamine derivatives showed no or only weak stimulatory effects on G-proteins. 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 agonists 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 derivatives on G-proteins are cell-type specific.
引用
收藏
页码:901 / 914
页数:14
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