Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.11 (AMPK)
 12,425 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of histamine on heart cAMP-dependent protein kinase activity, cAMP levels, phosphorylase activity, and contractile force was investigated in the perfused guinea pig heart. To accurately determine the protein kinase activity ratio in guinea pig heart, it was necessary to measure kinase activity in whole homogenates immediately after homogenization of the tissue. Histamine produced a rapid dose-dependent increase in cAMP and the protein kinase activity ratio followed by increased in contractile force and phosphorylase activity. There was a good correlation between the degree of protein kinase activation and the increase in phosphorylase and force. The beta-adrenergic blocking agent propranolol did not reduce the effects of histamine, but metiamide, a potent H2-receptor antagonist, greatly attenuated all the effects of histamine. The data support the hypothesis that increases in heart cAMP-dependent protein kinase activity produce corresponding increases in contractile force and phosphorylase activity.
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PMID:Involvement of cAMP-dependent protein kinase in the regulation of heart contractile force. II. 8 6

Sites at which the calcium-sensitive phospholipid-dependent protein kinase, protein kinase C, may influence acid secretion have been investigated in rat isolated parietal cells. In both crude and enriched preparations of parietal cells incubated in a medium containing 100 mM K+, the activators of protein kinase C, 12-O-tetradecanoylphorbol 13-acetate (TPA) and 1-oleoyl-2-acetyl-glycerol (OAG), produced a dose-dependent stimulation [half-maximally effective concentration (EC50) values of 1 nM and 70 microM, respectively] of aminopyrine accumulation, an index of the sequestration of acid in the cell. In a medium containing 4.5 mM K+, and with no added secretagogues, TPA and OAG did not affect aminopyrine accumulation. Histamine-stimulated aminopyrine accumulation was inhibited by TPA [half-maximally effective inhibitory concentration (IC50) of 2.9 nM]. TPA reduced the histamine-stimulation of the adenosine 3',5'-cyclic monophosphate (cAMP) content of parietal cells (47% inhibition at 100 nM TPA) but also inhibited aminopyrine accumulation at or distal to cAMP-dependent protein kinase. Activators of protein kinase C can produce multiple effects on secretory activity in the rat parietal cell.
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PMID:Sites of action of protein kinase C on secretory activity in rat parietal cells. 246 66

cAMP-dependent protein kinases have been characterized in parietal cells isolated from rabbit gastric mucosa. Both Type I and Type II cAMP-dependent protein kinase isozymes are present in these cells. Type II isozymes were detected in 900, 14,000, and 100,000 X g particulate fractions as well as 100,000 X g cytosolic fractions; Type I isozymes were found predominately in the cytosolic fraction. When parietal cells were stimulated with histamine, an agent that elevates intracellular cAMP content and initiates parietal cell HCl secretion, cAMP-dependent protein kinase activity was increased in homogenates of these cells as measured by an increase in the cAMP-dependent protein kinase activity ratio. Histamine activation of cAMP-dependent protein kinase was correlated with parietal cell acid secretory responses which were measured indirectly as increased cellular uptake of the weak base, [14C]aminopyrine. These results suggest that cAMP-dependent protein kinase(s) is involved in the control of parietal cell HCl secretion. The parietal cell response to histamine may be compartmentalized because histamine appears to activate only a cytosolic Type I cAMP-dependent protein kinase isozyme, as determined by three different techniques including 1) ion exchange chromatography; 2) Sephadex G-25 to remove cAMP and allow rapid reassociation of the Type II but not the Type I isozyme; and 3) 8-azido-[32P]cAMP photoaffinity labeling. Forskolin, an agent that directly stimulates adenylate cyclases, was found to activate both the Type I and Type II isozymes. Several cAMP-dependent protein kinases were also detected in parietal cell homogenates, including a Ca2+-phospholipid-sensitive or C kinase and two casein kinases which were tentatively identified as casein kinase I and II. At least two additional protein kinases with a preference for serine or lysine-rich histones, respectively, were also detected. The function of these enzymes in parietal cells remains to be shown.
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PMID:Parietal cell protein kinases. Selective activation of type I cAMP-dependent protein kinase by histamine. 298 57

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

Histamine H3 receptors modulate histamine synthesis, although little is known about the transduction mechanisms involved. To investigate this issue, we have used a preparation of rat brain cortical miniprisms in which histamine synthesis can be modulated by depolarization and by H3 receptor ligands. When the miniprisms were incubated in presence of forskolin, dibutyryl-cAMP, or 3-isobutyl-1-methylxanthine (IBMX), histamine synthesis was stimulated in 34, 29, and 47%, respectively. These stimulations could be prevented by the selective cAMP protein kinase blocker Rp-adenosine 3',5'-cyclic monophosphothioate triethylamine (Rp-cAMPs). Preincubation with the H3 receptor agonist imetit prevented IBMX- (100% blockade) and forskolin- (70% blockade) induced stimulation of histamine synthesis. The H3 inverse agonist thioperamide enhanced histamine synthesis in the presence of 1 mM IBMX or 30 mM potassium (+47 and +45%, respectively). Similarly, the H3 antagonist clobenpropit enhanced histamine synthesis in the presence of 30 mM potassium (+ 59%). The cAMP-dependent protein kinase blockers Rp-cAMPs and PKI14-22 could impair the effects of thioperamide and clobenpropit, respectively. These results indicate that the adenylate cyclase-protein kinase A pathway is involved in the modulation of histamine synthesis by H3 autoreceptors present in histaminergic nerve terminals.
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PMID:Presynaptic H3 autoreceptors modulate histamine synthesis through cAMP pathway. 1175 26

1. Histamine is generally regarded as a pro-inflammatory mediator in diseases such as allergy and asthma. A growing number of studies, however, suggest that this autacoid is also involved in the downregulation of human polymorphonuclear leukocyte (PMN) functions and inflammatory responses through activation of the Gs-coupled histamine H(2) receptor. 2. We report here that histamine inhibits thapsigargin- and ligand (PAF and fMLP)-induced leukotriene (LT) biosynthesis in human PMN in a dose-dependent manner. 3. The suppressive effect of histamine on LT biosynthesis was abrogated by the histamine H(2) receptor antagonists cimetidine, ranitidine, and tiotidine. In contrast, the histamine H(1), H(3), and H(4) receptor antagonists used in this study were ineffective in counteracting the inhibitory effect of histamine on the biosynthesis of LT in activated human PMN. 4. The inhibition of LT biosynthesis by histamine was characterized by decreased arachidonic acid release and 5-lipoxygenase translocation to the nuclear membrane. 5. Incubation of PMN with the cAMP-dependent protein kinase (PKA) inhibitor N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinoline-sulfonamide prevented the inhibitory effect of histamine on LT biosynthesis, suggesting an important role for PKA in this effect of histamine on LT biosynthesis in PMN. 6. These data provide the first evidences that, similarly to adenosine and prostaglandin E(2), histamine is a potent suppressor of LT biosynthesis, and support the concept that histamine may play a dual role in the regulation of inflammation.
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PMID:Histamine-induced inhibition of leukotriene biosynthesis in human neutrophils: involvement of the H2 receptor and cAMP. 1474 9

Using histamine and the H3 receptor antagonist thioperamide, the roles of histamine receptors in NMDA-induced necrosis were investigated in rat cultured cortical neurons. Within 3 h of intense NMDA insult, most neurons died by necrosis. Histamine reversed the neurotoxicity in a concentration-dependent manner and showed peak protection at a concentration of 10(-7) m. This protection was antagonized by the H2 receptor antagonists cimetidine and zolantidine but not by the H1 receptor antagonists pyrilamine and diphenhydramine. In addition, the selective H2 receptor agonist amthamine mimicked the protection by histamine. This action was prevented by cimetidine but not by pyrilamine. 8-Bromo-cAMP also mimicked the effect of histamine. In contrast, both the adenylyl cyclase inhibitor 9-(tetrahydro-2-furanyl)-9H-purine-6-amine and the cAMP-dependent protein kinase inhibitor N-[2-(p-bromocinnamylamino) ethyl]-5-isoquinolinesulfonamide reversed the protection by histamine. Thioperamide also attenuated NMDA-induced excitotoxicity, which was reversed by the H3 receptor agonist (R)-alpha-methylhistamine but not by pyrilamine and cimetidine. In addition, the protection by thioperamide was inhibited by the GABA(A) receptor antagonists picrotoxin and bicuculline. Further study demonstrated that the protection by thioperamide was due to increased GABA release in NMDA-stimulated samples. These results indicate that not only the H2 receptor/cAMP/cAMP-dependent protein kinase pathway but also the H3 receptor/GABA release pathway can attenuate NMDA-induced neurotoxicity.
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PMID:Histamine protects against NMDA-induced necrosis in cultured cortical neurons through H receptor/cyclic AMP/protein kinase A and H receptor/GABA release pathways. 1647 29

Histamine not only mediates immediate allergic reactions, it also regulates cellular immune responses. H4R is the most recently identified histamine receptor (HR). In the present study, we examined the in vitro effect of histamine and H4R agonists on the responses of human T cells to purified protein derivative from Mycobacterium tuberculosis (PPD) and to Cry j1, the major allergen of Cryptomeria japonica pollen. Dimaprit, clobenpropit and clozapine, which are H4R agonists, dose-dependently blocked both PPD-induced interferon-gamma and Cry j1-induced interleukin-5 production by both peripheral blood mononuclear cells (PBMCs) and antigen-specific T-cell lines. However, the addition of thioperamide, an H3R/H4R antagonist, as well as a mixture of d-chlropheniramine, famotidine and thioperamide, did not reverse the inhibition. Pretreatment of PBMCs with SQ22536 and 8-bromoadenosine-3',5'-cyclic monophosphorothioate, Rp-isomer, had varying abilities to reverse the inhibitory effects of H4R agonists, except for clobenpropit. Moreover, the addition of H4R agonists induced annexin-V expression on PBMCs, especially in CD19(+) and CD4(+) cells. cDNA microarray analysis revealed that, among 16,600 genes tested, increased expression following treatment with clozapine was seen in 0 x 8% of the genes, whereas decreased expression was seen in 3 x 0% of the genes. These results suggest that H4R agonists inhibit antigen-specific human T-cell responses, although H4R does not appear to be important for this effect. In addition, the present study indicated that there may be orphan receptors or HR subtypes which can bind dimaprit, clobenpropit and clozapine, and that can exert an inhibitory effect on antigen-specific cellular responses via a cAMP/cAMP-dependent protein kinase-dependent, apoptotic pathway.
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PMID:Histamine H4 receptor agonists have more activities than H4 agonism in antigen-specific human T-cell responses. 1734 80

Osteoblastic bone formation is important for maintaining the balance of bone turnover. However, the underlying mechanisms are still needed to be elucidated. Histamine H1 type receptor (H1R) is a major subtype of histamine membrane receptors family, which has displayed diverse biological functions in various tissues and cells. In the current study, we have identified a novel physiological function of H1R in regulating osteoblastic differentiation and mineralization of the MC3T3-E1 cells. We found that H1R is expressed in the MC3T3-E1 cells. Interestingly, H1R is up-regulated in the process of differentiation and mineralization of the MC3T3-E1cells induced by osteogenic medium (OM). Blockage of H1R using its specific antagonist Loratadine prevented differentiation and mineralization of the MC3T3-E1 cells by reducing ALP activity, bone matrix deposition, and the expressions of osteogenic marker genes including ALP, OCN, Osx, and type I collagen as well as the transcriptional factor RUNX-2, which is a central regulator of osteoblastogenesis. In contrast, we found that activation of H1R with Histamine exerts opposite actions by increasing the expressions of RUNX-2. Finally, we found that the effects of H1R in osteoblastic differentiation and mineralization are mediated by the AMPK/eNOS signaling. Based on these findings, we concluded that H1R might be an important therapeutic target for the treatment of skeletal disorders.
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PMID:The effects of histamine H1 type receptor (H1R) in regulating osteoblastic cell differentiation and mineralization. 3094 35