Regulation of histamine H₁ receptor-mediated phosphoinositide hydrolysis by histamine and phorbol esters in DDT₁ MF-2 cells

The regulation of histamine-stimulated phosphoinositide turnover by histamine and phorbol esters was examined in intact DDT₁ MF-2 cells grown in suspension culture. Histamine increased the incorporation of ³²P into phosphatidylinositol (PI) in these cells, and this stimulation was inhibited by the H₁ antagonist diphenhydramine but not by the H₂ antagonist cimetidine. Pretreatment of cells with histamine or with phorbol 12-myristate 13-acetate (PMA) or other activators of protein kinase C induced a marked decrease in the subsequent stimulation by histamine. PMA, but not histamine, also decreased the ability of epinephrine to stimulate PI labelling through α₁-adrenoceptors. Thus, histamine appears to induce homologous desensitization of histamine H₁ receptor-mediated PI turnover, whereas direct activation of protein kinase C in the absence of receptor occupancy by agonist induces nonspecific heterologous desensitization of both histamine H₁- and α₁-adrenoceptor-mediated responses.