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, chlorphenirami ne (CPHE) and diphenhydramine (DPH),may activate histamine release fro m basophils and mast cells. Because CPHE and DPH are cationic-amphiphi lic and because several substances with such physicochemical propertie s activate heterotrimeric regulatory guanine nucleotide-binding protei ns (G-proteins) in a receptor independent manner, we asked the questio n of whether or; not H-1-receptor antagonists could be G-protein activ ators as well. In dibutyryl cAMP differentiated HL-60 cells, CPHE and DPH increased cytosolic Ca2+ concentration and azurophilic granule rel ease in pertussis toxin (PTX)-sensitive manners. In HL-60 membranes, P TX sensitive stimulations of GTPase [E.C. 3.6.1.-] and binding of guan osine 5'-[gamma-thio]triphosphate by I-I, receptor antagonists were ob served. CPHE and DPH also increased GTP hydrolysis by the purified PTX sensitive G-protein, transducin. In all-trans-retinoic acid-different iated HL-60 cells and rat basophilic leukemia cells (RBL 2H3 cells), H -1-receptor antagonists induced, unlike in dibutyryl cAMP differentiat ed HL-60 cells, Ca2+ influx without Ca2+ mobilization from intracellul ar stores. CPHE and DPH also induced serotonin release from RBL 2H3 ce lls. Our data indicate that first-generation H-1-receptor antagonists are receptor-independent G-protein activators and that such a mechanis m of action accounts for their stimulatory effects in HL 60 cells, bas ophils, and mast cells.