The H1 receptor agonist 2-(3-chlorophenyl)histamine activates Gi proteins in HL-60 cells through a mechanism that is independent of known histamine receptor subtypes
Creators: name: Seifert, Roland
name: Hagelüken, A.
name: Höer, A.
name: Höer, D.
name: Grünbaum, L.
name: Offermanns, S.
name: Schwaner, I.
name: Zingel, V.
name: Schunack, W.
name: Schultz, Günter
Publisher: name: Universität Regensburg
Year: 1994
Subjects: subject: 610 Medizin
subject: 615 Pharmazie
subject: Calcium/metabolism
subject: Cell Membrane/drug effects
subject: Enzyme Activation/drug effects
subject: GTP-Binding Proteins/metabolism
subject: Glucuronidase/metabolism
subject: Glycerophospholipids
subject: Guanosine Triphosphate/metabolism
subject: Histamine/pharmacology
subject: Histamine Agonists/pharmacology
subject: Humans
subject: L-Lactate Dehydrogenase/metabolism
subject: Manganese/metabolism
subject: N-Formylmethionine Leucyl-Phenylalanine/pharmacology
subject: Pertussis Toxin
subject: Phosphatidic Acids/metabolism
subject: Phosphatidylinositols/metabolism
subject: Phosphotyrosine
subject: Receptors, Histamine H1/drug effects
subject: Respiratory Burst/drug effects
subject: Superoxides/metabolism
subject: Tumor Cells, Cultured
subject: Tyrosine/metabolism
subject: Virulence Factors, Bordetella/pharmacology

description: In dibutyryl-cAMP-differentiated HL-60 cells, histamine H1 and formyl peptide receptors mediate increases in the cytosolic Ca2+ concentration ([Ca2+]i) via pertussis toxin-sensitive G proteins of the Gi family. We compared the effects of 2-(3-chlorophenyl)-histamine (CPH) [2-[2-(3-chlorophenyl)-1H-imidazol-4-yl] ethanamine], one of the most potent and selective H1 receptor agonists presently available, with those of histamine and N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP) in these cells. CPH increased [Ca2+]i through Ca2+ mobilization and Ca2+ influx. Unlike histamine-induced rises in [Ca2+]i, those induced by CPH were not desensitized in a homologous manner, and there was no cross-desensitization between CPH and histamine. Like fMLP, CPH activated phospholipases C and D, tyrosine phosphorylation, superoxide anion formation, and azurophilic granule release. The effects of CPH on [Ca2+]i, phospholipase D, and superoxide anion formation were inhibited by pertussis toxin. CPH and fMLP stimulated high affinity GTP hydrolysis by Gi proteins in HL-60 membranes. They also enhanced binding of guanosine-5'-O-(3-thio)triphosphate and GTP azidoanilide to, and cholera toxin-catalyzed ADP-ribosylation of, Gi protein alpha subunits. Histamine receptor antagonists did not inhibit the stimulatory effects of CPH, and CPH did not reduce fMLP binding in HL-60 membranes. Our data suggest that CPH activates Gi proteins in HL-60 cells through a receptor agonist-like mechanism that is, however, independent of known histamine receptor subtypes and formyl peptide receptors. CPH may be an agonist at an as yet unknown histamine receptor subtype or, by analogy with other cationic-amphiphilic substances, may activate G proteins directly. Future studies will have to take into consideration the fact that CPH, in addition to activating H1 receptors, may show other, most unexpected, stimulatory effects on G protein-mediated signal transduction processes.