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
| Autor: | Seifert, R., Hageluken, A., Hoer, A., Hoer, D., Sergio Grunbaum, Offermanns, S., Schwaner, I., Zingel, V., Schunack, W., Schultz, G. |
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| Jazyk: | angličtina |
| Rok vydání: | 1994 |
| Předmět: |
Histamine/pharmacology
Phosphatidylinositols/metabolism Calcium/metabolism 610 Medizin Glycerophospholipids Manganese/metabolism 615 Pharmazie L-Lactate Dehydrogenase/metabolism Tumor Cells Cultured Humans Respiratory Burst/drug effects Phosphotyrosine Histamine Agonists/pharmacology ddc:610 Cell Membrane/drug effects Phosphatidic Acids/metabolism Virulence Factors Bordetella/pharmacology ddc:615 Receptors Histamine H1/drug effects Pertussis Toxin Guanosine Triphosphate/metabolism Glucuronidase/metabolism Enzyme Activation/drug effects GTP-Binding Proteins/metabolism Superoxides/metabolism N-Formylmethionine Leucyl-Phenylalanine/pharmacology Tyrosine/metabolism |
| Zdroj: | Scopus-Elsevier |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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