Disease relevance of HRH2

• In anaphylaxis histamine H1-receptor stimulation can mediate vascular permeability, smooth muscle contraction, and tachycardia, whereas H2-receptor stimulation can mediate mucus secretion [1].
• Of the four cardinal signs of asthma (bronchospasm, edema, inflammation, and mucus secretion), histamine is capable of mediating the first two through its H1 receptor and mucus secretion through its H2 receptor [1].
• Histamine elevates the expression of Ets-1, a protooncogen in human melanoma cell lines through H2 receptor [2].
• We found that a 85 bp segment (-610-(-)525 bp) immediately upstream of the initiation site exhibits a strong promoter activity in the gastric adenocarcinoma, MNK45, expressing human histamine H2 receptor [3].
• These data imply that an histamine-induced, H2-receptor-mediated suppressor circuit often helps modulate antigen-specific responsiveness of PBMN from patients with chronic schistosomiasis [4].

Psychiatry related information on HRH2

• CONCLUSIONS: This study demonstrates the lack of effect of peripheral administration of H2-receptor antagonists on sleep stages, while subjective or objective assessment of daytime alertness revealed small effects of famotidine and cimetidine [5].
• Results of epidemiological studies have shown that long-term use of non-steroidal anti-inflammatory drugs, statins, histamine H2-receptor blockers, or calcium-channel blockers seems to prevent Alzheimer's disease [6].
• Those individuals who do seek medical advice for reflux symptoms will probably receive a prescription for an H2-receptor antagonist, although in many instances simple life-style changes and occasional use of antacids may provide effective therapy [7].
• The effects of histamine and the selective H2 receptor agonist dimaprit on free-running locomotor activity rhythms were monitored [8].
• In Huntington's chorea, the levels of histamine H2-receptor binding sites were found to be markedly decreased in virtually all regions examined, particularly in the putamen and globus pallidus lateralis [9].

High impact information on HRH2

• METHODS: In a multicenter, randomized, blinded, placebo-controlled trial, we compared sucralfate with the H2-receptor antagonist ranitidine for the prevention of upper gastrointestinal bleeding in 1200 patients who required mechanical ventilation [10].
• There are conflicting data on the effect of histamine H2-receptor antagonists and the cytoprotective agent sucralfate on rates of gastrointestinal bleeding, ventilator-associated pneumonia, and mortality [10].
• A history of gastrointestinal complications attributed to cystic fibrosis and the use of histamine H2-receptor blockers, corticosteroids, or recombinant human DNase (dornase alfa) were associated with a higher incidence of fibrosing colonopathy [11].
• Acid suppression with famotidine, a histamine H2-receptor antagonist, provides protection against gastric injury in normal subjects receiving short courses of aspirin or naproxen [12].
• Hemorrhage is the most common complication of duodenal ulcer disease, but there is little information about the effectiveness and safety of long-term maintenance therapy with histamine H2-receptor blockers [13].

Chemical compound and disease context of HRH2

• H2 receptor blockade with cimetidine does not appear to affect ventilatory function or bronchial hyperreactivity to histamine in asthmatic subjects [14].
• 4 Histamine H2-receptor agonists, impromidine and dimaprit, produced hyperthermia which was antagonized by cimetidine [15].
• Ingestion of ranitidine markedly reduces vasodilation after exercise and blunts postexercise hypotension, suggesting H2-receptor-mediated vasodilation contributes to postexercise hypotension [16].
• STUDY OBJECTIVE: We compared the efficacies of cimetidine (an H2-receptor antagonist) and diphenhydramine (an H1-receptor antagonist) alone and in combination for alleviation of symptoms of acute allergic reactions [17].
• Eighteen patients with atopic dermatitis were randomly chosen for a clinical trial to compare the action of the H2 receptor antagonist cimetidine in combination with the H1 receptor antagonist chorpheniramine against the chlorpheniramine alone and against placebo [18].

Biological context of HRH2

• Because of the rapid nature of H2r desensitization, receptor phosphorylation was examined as a likely mechanism for signal attenuation [19].
• Nitric oxide mediates histamine induced down-regulation of H2 receptor mRNA and internalization of the receptor protein (R1) [20].
• However, hH2R poorly coupled to insect Gq-proteins as assessed by the lack of enhancement of histamine-stimulated steady-state GTP hydrolysis by regulators of G protein signaling (RGS proteins) [21].
• The role of nitric oxide (NO) as a key mediator in histamine-stimulated cell responses was underlined by subsequent studies showing the attenuation of histamine-induced H2 receptor mRNA down-regulation and protein trafficking following NO synthase isozyme inhibition [20].
• Alteration of intracellular histamine H2 receptor cycling precedes antagonist-induced upregulation [22].

Anatomical context of HRH2

• Recent reports showed effects of histamine on human monocyte-derived dendritic cells (MoDC) mediated primarily via histamine H1 receptors (H1R) and H2R [23].
• Using transiently transfected COS-7 cells expressing tagged-H2r, the desensitization induced by amthamine, characterized by decreased cAMP production, was studied [19].
• We were able to show that the histamine-induced down-regulation of H2 receptor mRNA and cell surface expression lasting for 24 h was accompanied by augmentation of the receptor protein level in the cytoplasmatic fraction of endothelial cells for this time period [20].
• Long-term administration of a histamine H2 receptor (H2R) antagonist (inverse agonist) induces upregulation of H2R in parietal cells, which may be relevant to the rebound hypersecretion of gastric acid that occurs after withdrawal of treatment [22].
• A 4.8 kb transcript of the human histamine H2 receptor gene was found in the placenta, spinal cord, lymph node and bone marrow in addition to the previously reported tissues including the heart, brain and stomach, whereas a 1.8 kb transcript was observed in almost all tissues examined [3].

Associations of HRH2 with chemical compounds

• Denatured AT-III did not bind HRH2, indicating that its heparin recognition site may depend on conformation [24].
• Stimulation of dendritic cells with histamine resulted in F-actin polymerization and cyclic adenosine monophosphate production through H2R [25].
• H2r desensitization was not affected by protein kinases A and C (PKA and PKC) inhibitors but was remarkably reduced by Zn(2+), an inhibitor of G protein-coupled receptor kinases (GRKs) [19].
• Histamine-induced increase of cAMP was inhibited by the H2 receptor antagonist famotidine, whereas induction of IP3 was not observed, making signaling via the H1 receptor unlikely [26].
• The binding affinity of [3H]tiotidine was not significantly different between H2R-GFP- and wild-type H2R-expressing HEK-293 cells, both of which had constitutive activity of adenylate cyclase [22].

Physical interactions of HRH2

• Small H1R agonists and 2-phenylhistamines interacted differentially with human and guinea pig H2R in terms of potency and efficacy, respectively [27].
• Significant elevation of MS ADCC by cimetidine alone suggested that endogenous histamine production and H2 receptor binding could be mediating a suppressive effect on MS ADCC to oligodendrocytes [28].
• Tiotidine, a histamine H2 receptor inverse agonist that binds with high affinity to an inactive G-protein-coupled form of the receptor. Experimental support for the cubic ternary complex model [29].
• This interference clearly implies that tiotidine biases the system to Galphas-coupled form of the H2 receptor and turns Galphas-protein less available to interact with beta2-adrenoreceptor [29].
• A new model for the agonistic binding site on the histamine H2-receptor: the catalytic triad in serine proteases as a model for the binding site of histamine H2-receptor agonists [30].

Regulatory relationships of HRH2

• The alteration of the responsiveness of LOX-1 expression to histamine was related to suppressed expression of the H2 receptor in THP-1 macrophages [31].
• Recent investigations suggest that H1R signaling on lymphocytes may enhance whereas activation of the H2R may inhibit lymphocyte responses [32].
• The H1 receptor is involved not only in allergic inflammatory reactions but also in augmentation of helper T cell (Th)1 responses, whereas H2 receptor suppresses Th responses and participates in immune tolerance through interleukin-10 and transforming growth factor-beta [33].
• Selective activation of H1 receptors by combined infusion of HA and the H2 receptor antagonist cimetidine stimulated PRL secretion (delta PRL, 193 +/- 40 vs. -20 +/- 17 microIU/ml; P less than 0.0005; n = 6) [34].
• Effect of histamine H2-receptor stimulation on bombesin- and peptone-stimulated gastrin release in man [35].

Other interactions of HRH2

• H4R or H2R stimulation suppressed IL-12p70 production in MoDC [23].
• These results indicate that in H2r-transfected COS-7 cells, exposure to an agonist caused desensitization controlled by H2r phosphorylation via GRK2 and GRK3 [19].
• Histamine increases the expression of LOX-1 via H2 receptor in human monocytic THP-1 cells [31].
• On U937 cells, using a monoclonal antibody reacting with the 80 kd chain of the human IL-6 receptor, and H2-receptor mediated inhibition of IL-6 receptor expression was found by FACS analysis [36].
• Like other G protein-coupled receptors, exposure of H2r to agonists produces a desensitization of the response [19].

Analytical, diagnostic and therapeutic context of HRH2

• METHODS: Expression of histamine H1 and H2 receptors (H1R and H2R) on MoDCs was assessed by means of RT-PCR and flow cytometry [25].
• Following PCR amplification of a fragment of the H2R gene from total human DNA, three single nucleotide base substitutions were observed and confirmed when compared with the previously published sequence [37].
• Molecular cloning of the human histamine H2 receptor [38].
• Northern blot analysis identified a single transcript of 4.6 kb in peripheral tissues and brain areas in which the presence of the H2 receptor had been revealed previously by either photoaffinity labeling or binding studies [39].
• In brain, the distribution of transcripts, established by either Northern blots or in situ hybridization studies, was consistent with the localization of the H2-receptor [39].

References