title: Receptor-independent G protein activation may account for the stimulatory effects of first-generation H1-receptor antagonists in HL-60 cells, basophils, and mast cells.
abstract: The first-generation histamine H1-receptor antagonists, chlorpheniramine (CPHE) and diphenhydramine (DPH), may activate histamine release from basophils and mast cells. Because CPHE and DPH are cationic-amphiphilic and because several substances with such physicochemical properties activate heterotrimeric regulatory guanine nucleotide-binding proteins (G-proteins) in a receptor-independent manner, we asked the question of whether or not H1-receptor antagonists could be G-protein activators as well. In dibutyryl cAMP-differentiated HL-60 cells, CPHE and DPH increased cytosolic Ca2+ concentration and azurophilic granule release in pertussis toxin (PTX)-sensitive manners. In HL-60 membranes, PTX-sensitive stimulations of GTPase [E.C. 3.6.1.] and binding of guanosine 5'-[gamma-thio]triphosphate by H1 receptor antagonists were observed. CPHE and DPH also increased GTP hydrolysis by the purified PTX-sensitive G-protein, transducin. In all-trans-retinoic acid-differentiated HL-60 cells and rat basophilic leukemia cells (RBL 2H3 cells), H1-receptor antagonists induced, unlike in dibutyryl cAMP-differentiated HL-60 cells, Ca2+ influx without Ca2+ mobilization from intracellular stores. CPHE and DPH also induced serotonin release from RBL 2H3 cells. Our data indicate that first-generation H1-receptor antagonists are receptor-independent G-protein activators and that such a mechanism of action accounts for their stimulatory effects in HL-60 cells, basophils, and mast cells.
authors.affiliation: Institut für Pharmakologie, Universitätsklinikum Benjamin Franklin, Freie Universität Berlin, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Burde
authors.forename: E
authors.initials: E
authors.lastname: Dippel
authors.forename: R
authors.initials: R
authors.lastname: Seifert
mesh_terms: D000818:Animals; D001491:Basophils; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured / Q000187:drug effects; D002744:Chlorpheniramine / Q000494:pharmacology; D004155:Diphenhydramine / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism*; D018922:HL-60 Cells; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D006801:Humans; D008407:Mast Cells; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D037342:Pertussis Toxin; D051381:Rats; D012701:Serotonin / Q000378:metabolism; D013997:Time Factors; D015293:Transducin / Q000494:pharmacology; D010566:Virulence Factors, Bordetella
chemical_list: D006634:Histamine H1 Antagonists; D010566:Virulence Factors, Bordetella; D012701:Serotonin; D002744:Chlorpheniramine; D009240:N-Formylmethionine Leucyl-Phenylalanine; D004155:Diphenhydramine; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D015293:Transducin; D002118:Calcium