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

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

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17 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)27-32
Number of pages6
JournalBiochemical Journal
Volume320
Issue number1
DOIs
Publication statusPublished - 1996 Nov 15

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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