The histamine H2 receptor is a member of the family of G-protein-coupled receptors and is linked to the activation of adenylate cyclase phospholipase C (PLC). In this study we examined the effects of protein kinase C (PKC) activation in Chinese hamster ovary (CHO) cells stably expressing canine histamine H2 receptors. Pretreatment with 100 nM phorbol 12-myristate 13-acetate at 37 °C for 15 min led to significant potentiation of histamine-dependent and forskolin-dependent cAMP production, whereas the biologically inactive phorbol ester, 4α-phorbol 12,13-didecanoate, was without effect. These potentiating effects were abolished by preincubation with 0.5 µM 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 mechanism. Preincubation of a CHO cell line, CHO-H2R, with 10 µM histamine for 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 histamine-dependent adenylate cyclase response as demonstrated by a three-fold increase in EC50. Administration of 0.5 µM bisindolylmaleimide before preincubation of CHO-H2R with 10 µM histamine did not alter the desensitizing effect on cAMP production, but did abolish the sensitizing effect. Preincubation of CHO-H2R cells with 10 nM histamine resulted in moderate potentiation, which was also abolished by bisindolylmaleimide, but not in desensitization of the histamine-dependent cAMP production. Thus these results suggest that preincubation with histamine 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 concentration of histamine.
Interaction between the two 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
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Yasushi FUKUSHIMA, Tomoichiro ASANO, Hideki KATAGIRI, Makoto AIHARA, Toshihito SAITOH, Motonobu ANAI, Makoto FUNAKI, Takehide OGIHARA, Kouichi INUKAI, Nobuyuki MATSUHASHI, Yoshitomo OKA, Yoshio YAZAKI, Kentaro SUGANO; Interaction between the two 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. Biochem J 15 November 1996; 320 (1): 27–32. doi: https://doi.org/10.1042/bj3200027
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