INTERACTION BETWEEN THE 2 SIGNAL-TRANSDUCTION SYSTEMS OF THE HISTAMINE-H2-RECEPTOR - DESENSITIZING AND SENSITIZING EFFECTS OF HISTAMINE STIMULATION ON HISTAMINE-DEPENDENT CAMP PRODUCTION IN CHINESE-HAMSTER OVARY CELLS

The histamine H2 receptor is a member of the family of G-protein-coupl ed receptors and is linked to the activation of adenylate cyclase phos pholipase C (PLC). In this study we examined the effects of protein ki nase C (PKC) activation in Chinese hamster ovary (CHO) cells stably ex pressing canine histamine H2 receptors. Pretreatment with 100 nM phorb ol 12-myristate 13-acetate at 37 degrees C for 15 min led to significa nt potentiation of histamine-dependent and forskolin-dependent cAMP pr oduction, whereas the biologically inactive phorbol ester, 4 alpha-pho rbol 12,13-didecanoate, was without effect. These potentiating effects were abolished by preincubation with 0.5 mu M bisindolylmaleimide, a PKC inhibitor. Thus the activation of PKCs seems to be involved in the potentiation of cAMP production by acting on a post-receptor mechanis m. Preincubation of a CHO cell line, CHO-H2R, with 10 mu M histamine f or 30 min had two effects. Maximal histamine-dependent cAMP production and forskolin-dependent cAMP production were potentiated by 36 % and 105.2 % respectively. The other effect was a desensitization of the hi stamine-dependent adenylate cyclase response as demonstrated by a thre e-fold increase in EC(50). Administration of 0.5 mu M bisindolylmaleim ide before preincubation of CHO-H2R with 10 mu M histamine did not alt er the desensitizing effect on cAMP production, but did abolish the se nsitizing effect. Preincubation of CHO-H2R cells with 10 nM histamine resulted in moderate potentiation, which was also abolished by bisindo lylmaleimide, but not in desensitization of the histamine-dependent cA MP production. Thus these results suggest that preincubation with hist amine had a sensitizing effect on cAMP production mediated by PLC and PKC activation, as well as a desensitizing effect on the H2 receptor. The former effect is dependent on the intensity of PLC and PKC signals delivered by H2 receptors. The latter effect requires a higher concen tration of histamine.