Receptor-independent G protein activation may account for the stimulatory effects of first-generation H-1-receptor antagonists in HL-60 cells, basophils, and mast cells

The first-generation histamine Hi-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 H-1-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 I-I, 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), H-1-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 H-1-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.