Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Histamine receptor-mediated modulation of the delayed outward potassium current (IK) was investigated in guinea-pig single ventricular cells by the whole-cell voltage clamp. 2. Histamine increased IK in a dose- dependent manner with a half-maximum dose of 3.8 x 10(-8) M. Histamine (10(-6) M) increased IK by a factor of 3.02 without a significant change in the current kinetics. The threshold dose of histamine for increasing IK was 10(-9) M and this value was similar to that for calcium current. 3. Cimetidine decreased IK in the presence of histamine, by shifting the dose-response curve to histamine to the right. The pA2 value of cimetidine against histamine was 6.38. 4. Forskolin did not increase IK after application of 10(-6) M histamine, and histamine scarcely increased IK in the presence of a heat-stable inhibitor of cyclic AMP-dependent protein kinase (PKI). 5. We conclude that stimulation by histamine of IK is mainly by way of the H2-receptor, and is mediated by cyclic AMP-dependent phosphorylation.
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PMID:Modulation by histamine of the delayed outward potassium current in guinea-pig ventricular myocytes. 809 39

In the immune system, histamine is known to suppress cytotoxic T-lymphocytes and nitrogen induced lymphocyte thymidine uptake, down-regulate some cytokines, and activate suppressor T-lymphocytes, and in the gastrointestinal system, histamine was reported to have trophic effects on gastrointestinal epithelial cells. Enhanced rates of cell proliferation by histamine are implicated in the pathogenesis. This study was designed since there is a lack of comparative data about the cell proliferations of histamine-2 receptor antagonist (H2-RA), cimetidine, ranitidine, and famotidine, in gastric cancer. KATO-III and AGS cell lines were used in this experiment. The concentrations of the histamine and cimetidine were 10(-5)-10(-8) M, respectively and those of ranitidine and famotidine were 10(-6)-10(-9)M, respectively. Cell proliferation after drug treatment was evaluated by direct cell counting, [3H]thymidine incorporation, and MTT assay. Activities of ornithine decarboxylase (ODC), a rate limiting enzyme in polyamine synthesis, were measured after each drug treatment. Protein kinase A, a cAMP-dependent protein kinase system, was assayed using [alpha-32P]ATP. Histamine showed statistically significant cell proliferating effects in a dose-dependent manner (P < 0.001), the maximal effect in 10(-5) M concentration. ODC activities were increased in accordance with the increment of cell numbers after histamine treatment. Cimetidine reversed the histamine-stimulated cell proliferation significantly, the maximal effect in 10(-5) M concentration (P < 0.01). Although ranitidine showed the tendency to attenuate the cell proliferation dose-dependently, but without statistical significance, famotidine did not show such an effect at all. cAMP-dependent protein kinase activities were significantly increased following 10(-5) M histamine treatment, also reversed significantly by cimetidine co-administration (P < 0.01). Beneficial clinical outcomes could be anticipated from cimetidine treatment in patients with gastric cancer by anti-proliferating effects against gastric cancer cells. These effects of H2-RA are likely to be mediated by specific interactions at the H2-receptor.
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PMID:Comparison of antiproliferative effects of 1-histamine-2 receptor antagonists, cimetidine, ranitidine, and famotidine, in gastric cancer cells. 902 41

Interferon-induced protein of (IP-10) inhibits tumor progression. Tumor cells can produce interferon-induced protein of IP-10 in response to interferon-g. Histamine in the vicinity of tumor cells may sustain the tumor progression. We examined the in vitro effects of histamine on interferon-induced protein of IP-10 production in human squamous cell carcinoma and melanoma. Histamine suppressed interferon-g-mediated interferon-induced protein of IP-10 secretion and mRNA expression in SV40-transformed keratinocytes, SCC15, SCC4, and melanoma WM115, WM266-4, and C32. Histamine suppressed interferon-g-induced interferon-mediated protein of IP-10 promoter activation in these cells, and the interferon-stimulated response element on the promoter was responsible for the suppression. Histamine suppressed interferon-g-mediated transcription through the interferon-stimulated response element and signal transducer and activator of transcription 1alpha binding to the interferon-stimulated response element. Histamine suppressed interferon-g-induced tyrosine phosphorylation of the signal transducer and activator of transcription 1alpha, Janus tyrosine kinase 1, and Janus tyrosine kinase 2. Histamine-mediated suppression on the interferon-g-induced interferon-mediated protein of IP-10 synthesis was counteracted by the H2 receptor antagonist cimetidine, adenylate cyclase inhibitor SQ22536, and protein kinase A inhibitor H-89, but were not affected by H1 receptor antagonist mepyramine. Cimetidine, SQ22536, and H-89 also counteracted histamine-mediated suppression on the interferon-g-induced transcription through the interferon-stimulated response element, signal transducer and activator of transcription 1alpha binding to the interferon-stimulated response element, and tyrosine phosphorylation of the signal transducer and activator of transcription 1alpha, Janus tyrosine kinase 1, and Janus tyrosine kinase 2. Histamine increased intracellular 3',5'-adenosine cyclic monophosphate level and protein kinase A activity in squamous cell carcinoma and melanoma, and the effects of histamine were blocked by cimetidine. These results suggest that histamine may interact with H2 receptor on squamous cell carcinoma and melanoma and generate 3',5'-adenosine cyclic monophosphate, which may activate protein kinase A. The cyclic 3',5'-adenosine monophosphate/protein kinase A signaling pathway induced by histamine may inhibit interferon-g-induced signal transducer and activator of transcription 1alpha activation and suppress interferon-induced protein of IP-10 synthesis.
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PMID:Histamine inhibits the production of interferon-induced protein of 10 kDa in human squamous cell carcinoma and melanoma. 1248 48

The present study demonstrates a possible mechanism for the improvement of gastrointestinal cancer patients' prognosis by the histamine receptor type 2 (H2R) antagonist cimetidine. This agent, but not the H2R antagonists ranitidine and famotidine, induced the production of an antitumor cytokine, interleukin (IL)-18, by human monocytes and dendritic cells (DC). In fact, ranitidine and famotidine antagonized cimetidine-induced IL-18 production. Cimetidine induced the activation of caspase-1, which is reported to modify immature IL-18 to mature/active IL-18, and the elevation of intracellular cAMP, leading to the activation of protein kinase A (PKA). The PKA inhibitor H89 abolished the IL-18 production induced by cimetidine. Moreover, the effects of cimetidine on IL-18 production were reproduced in peripheral blood mononuclear cells from wild-type mice, but not in those from H2R knockout mice. In conclusion, cimetidine, a partial agonist for H2R, has a pharmacological profile different from ranitidine and famotidine, possibly contributing to its antitumor activity on gastrointestinal cancers.
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PMID:Cimetidine induces interleukin-18 production through H2-agonist activity in monocytes. 1672 95