Lack of association between atopic asthma and polymorphisms of the histamine H1 receptor, histamine H2 receptor, and histamine N-methyltransferase genes.
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Asthma↗
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Results for “Receptors, Histamine H2”
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Inverse agonism of histamine H2 antagonist accounts for upregulation of spontaneously active histamine H2 receptors.
Histamine H2 receptors transfected in Chinese hamster ovary (CHO) cells are time- and dose-dependently upregulated upon exposure to the H2 antagonists cimetidine and ranitidine. This effect appears to be H2 receptor-mediated as no change in receptor density was observed after H1 or H3 antagonist treatment or after incubation with the structural analogue of cimetidine, VUF 8299, which has no H2 antagonistic effects. By using transfected CHO cells expressing different densities of wild-type H2 receptors or an uncoupled H2Leu124Ala receptor, the histamine H2 receptor was found to display considerable agonist-independent H2 receptor activity. Cimetidine and ranitidine, which both induce H2 receptor upregulation, actually functioned as inverse agonists in those cell lines displaying spontaneous agonist-independent H2 receptor activity. Burimamide, on the other hand, was shown to act as a neutral antagonist and did as expected not induce H2 receptor upregulation after long-term exposure. The displayed inverse agonism of H2 antagonists appears to be a mechanistic basis for the observed H2 antagonist-induced H2 receptor upregulation in transfected CHO cells. These observations shed new light on the pharmacological classification of the H2 antagonists and may offer a plausible explanation for the observed development of tolerance after prolonged clinical use.
Animals↗
Visualization of agonist-induced internalization of histamine H2 receptors.
Histamine H2 receptors were tagged at the N-terminus with the eight amino acid Flag epitope to allow the immunological identification of the receptor peptide with the monoclonal anti-Flag M2 antibody. The introduction of the epitope did not modify the binding of several H2 ligands to the H2 receptor, nor the ability of histamine to stimulate the H2 receptor mediated cAMP production in HEK-293 cells. Western blots revealed a major protein band of 57 +/- 1 kDa, whereas a second band of 31 +/- 1 kDa was probably the result of a proteolytic breakdown of the 57 kDa band. Immunofluorescence measurements of stably transfected HEK-293 cells revealed the presence of anti-Flag-immunoreactivity in the plasma membrane. This immunoreactivity completely disappeared after a one hour treatment with histamine. The receptor internalization was reversible and blocked by the endocytosis inhibitor phenylarsine oxide. Forskolin did not induce H2 receptor internalization, indicating that histamine causes H2 receptor internalization via a cAMP-independent pathway.
Amino Acid Sequence↗
Multiple signaling pathways of histamine H2 receptors.
Histamine H2 receptor (H2R) has been shown to be coupled to adenylate cyclase. However, we have previously demonstrated that H2R-specific stimulation also activated phospholipase C in human HL-60 promyelocytic leukemia cells (Mitsuhashi M. et al. J. Biol. Chem. 264:18356, 1989). We have extended these studies on HL-60 cells to investigate whether histamine-bovine serum albumin conjugates (HA-BSA) specifically recognize H2R and activate phospholipase C pathways. Both histamine (HA) and HA-BSA increased intracellular concentrations of calcium in a H2R specific manner. However, HA-induced calcium mobilization was transient and returned to the basal level within 1-2 min, whereas HA-BSA-induced calcium mobilization was sustained for more than 10 min as a result of the additional influx of extracellular calcium. More interestingly, fluorescein (FITC) labeled HA-BSA was less incorporated into cytosols and present in the membrane fractions for more than 60 min, whereas membrane-bound FITC-HA was rapidly incorporated into cytosols. Furthermore, the levels of inositol 1,3,4,5-tetrakisphosphate, which is known to activate calcium channels were more sustained after HA-BSA stimulation than those of HA alone. These data suggest that H2R activation mechanism is more complex and may be modified by this slowly metabolized "compound ligand".
Calcium↗
[Regulation of gastric juice secretion by gastric wall cell receptors--histamine H2 receptors, muscarine- and gastrin receptors].
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Animals↗
Histamine suppresses gene expression and synthesis of tumor necrosis factor alpha via histamine H2 receptors.
Histamine and tumor necrosis factor alpha (TNF-alpha) can each contribute to the pathogenesis of allergic reactions and chronic inflammatory diseases. We now report the effect of histamine on gene expression and total cellular synthesis of TNF-alpha. Lipopolysaccharide (LPS)-induced synthesis of TNF-alpha in peripheral blood mononuclear cells (PBMC) from 18 healthy donors was suppressed by histamine concentrations from 10(-6) to 10(-4) M, levels comparable with those measured in tissues after mast cell degranulation. Histamine (10(-5) M) markedly suppressed LPS-induced synthesis of TNF-alpha in both unfractionated PBMC (83% inhibition, p less than 0.001) and monocytes purified by positive selection of LeuM3+ cells (62% inhibition, p less than 0.05). The suppressive effect of histamine on TNF-alpha synthesis did not require the presence of T cells. The histamine-mediated decrease in TNF-alpha synthesis was not affected by indomethacin, nor by diphenhydramine, an H1 receptor antagonist, but was reversed by cimetidine or ranitidine, H2 receptor antagonists, in a dose-dependent manner. Suppression of TNF-alpha synthesis by histamine is likely to be a transcriptional event, since histamine (10(-5) M) reduced TNF-alpha mRNA levels fourfold. These results suggest that histamine release from mast cells may paradoxically limit the extent of inflammatory and immune reactions by suppressing local cytokine synthesis in H2 receptor-bearing cells.
Cells, Cultured↗
Construction of a novel bifunctional biogenic amine receptor by two point mutations of the H2-histamine receptor.
BACKGROUND: H2-histamine receptors mediate a wide range of physiological functions extending from stimulation of gastric acid secretion to induction of human promyelocyte differentiation. We have previously cloned the H2-histamine receptor gene and noted that only three amino acids on the receptor were sufficient to define its specificity and selectivity. Despite only modest overall amino acid homology (34% amino acid identity and 57.5% similarity) between the H2-histamine receptor and the receptor for another monoamine, the beta 2-adrenergic receptor, there is remarkable similarity at their critical ligand binding sites. We hypothesized that, if the specificity and selectivity of both receptors are invested in just three amino acids, it should be possible to convert one of the receptors into one that recognizes the ligand of the other by simple mutations at only one or two sites. MATERIAL AND METHODS: We explored the effect of two single mutations in the fifth transmembrane domain of the H2-histamine receptor, which encompasses the sites that determine H2 selectivity. The canine H2 receptor gene was mutated at Asp186 and Gly187 (Asp186 to Ala186 and Gly187 to Ser187) by oligonuceotide directed mutagenesis. The coding region of both the wild-type and mutated H2 receptors was subcloned into the eukaryotic expression vector, CMVneo, and stably transfected into Hepa cells and L cells. The biological activity of histamine and epinephrine on the expressed receptor was examined by measurement of cellular cAMP production and inositol trisphosphate formation. RESULTS: Hepa cells transfected with the Ala186-Ser187 mutant H2 receptor demonstrated a biphasic rise in cAMP in response to epinephrine with an early phase (ED50 approximately 10(-11) M) that could be inhibited by both propranolol and cimetidine. Epinephrine also induced IP3 generation in the same cells, a biological response that is characteristic of activation of the wild-type H2 but not of the beta-adrenergic receptor. L cells transfected with the Ala186-Ser187 mutant H2 receptor also responded to epinephrine in a cimetidine and propranolol inhibitable manner. CONCLUSIONS: We converted the H2-histamine receptor into a bifunctional one that has characteristics of both histamine and adrenergic receptors by two simple mutations. These results support the hypothesis that ligand specificity is determined by only a few key points on a receptor regardless of the structure of the remainder of the molecule. Our studies have important implications on the design of pharmacological agents targeted for action at physiological receptors.
Adrenergic beta-Antagonists↗
Dimaprit analogues inhibit tyrosinase via a disulphide breakdown product independently of the histamine H2 receptor.
Histamine displayed specific and saturable binding to membrane fractions of the human melanoma cell line MM96E (Kd = 72.4 nM and Bmax = 487 fmol/mg protein). There was weak competition with isothioureas that inhibit tyrosinase in intact cells: dimaprit (an H2 agonist) nordimaprit and S-[2-(N,N-diisopropyl)ethyl]isothiourea (DINOR). Under culture conditions, rapid, pH-dependent hydrolysis of the isothioureas occurred, with cleavage to urea and a thiol which spontaneously oxidised to the disulphide. The H3 agonist imetit, which also inhibited tyrosinase, behaved similarly. The disulphide breakdown product of DINOR but not the thiol inhibited tyrosinase activity in intact MM96E cells to a similar extent as DINOR itself. Isothioureas with more bulky substituents, however, were stable in culture and did not inhibit tyrosinase. The results show that (a) certain histaminergic drugs exert effects via a disulphide hydrolysis product independently of the histamine H2 receptor, and (b) beta-aminoethyldisulphides are depigmenting agents.
Biotransformation↗
Method for detection of antibody against low molecular weight antigen (hapten)--production and detection of antibody against histamine H2 receptor of antibody against histamine H2 receptor antagonist "Famotidine".
Antibodies against histamine H2-receptor antagonist "Famotidine (FAMO)", molecular weight 337, chemical name; N-sulfamoyl-3-(2-guanidinothiazol-4-ylmethylthio) propionamide, were produced by subcutaneously injecting rabbits with an albumin and FAMO conjugate covalently bound with 1-ethyl-3-(3-dimethyl-amino-propyl) carbodiimide (ECDI). Two new detection systems for antibody titration were developed and employed. In one method, the antigen FAMO was tagged to sheep red blood cells (SRBC) and analysed qualitatively by a fluorescence activated cell sorter (FACS) using a second fluorescence isothiocyanate (FITC) labeled antibody. In the other method, CH-Sepharose beads were employed in place of SRBC and Horse Radish Peroxidase (HRP) was labeled to the second antibody instead of FITC used in the former method. HRP of the immune complex was colorimetrically measured with DAB-H2O2 to analyse the fine antibody titer. These high sensitive detection methods revealed the existence of IgG type of FAMO antibody. The detection sensitive detection methods revealed the existence of IgG type of FAMO antibody. The detection sensitivity was approximately 50 to 100 times higher in the later method with HRP than in the former. Furthermore these two methods could be deemed to be a good model system for a receptor assay.
Animals↗
[Functional analyses of gastric mucosa using mice deficient in both histamine H2 receptor and CCKB/gastrin receptor].
Histamine H2 and cholecystokinin (CCK)-B/gastrin receptors are very important in both acid secretion and growth and differentiation of the gastric mucosa. Generations of mice deficient in each of these receptors have provided information on the structure and function of the gastric mucosa, respectively. To examine the gastric mucosa in further detail, we generated mice deficient in both receptors. This review discusses the roles of histamine H2 and CCK-B/gastrin receptors in gastric mucosa based on data from our double-null mice.
Animals↗
Histamine H2 receptor antagonism by T-593: studies on cAMP generation in Hepa cells expressing histamine H2 receptor.
Histamine H2 receptor antagonism by T-593 was investigated in Hepa cells expressing canine histamine H2 receptors. T-593 inhibited generation of cAMP in Hepa cells stimulated by 10(-5) mol/l histamine with an IC50 value of 2.3 x 10(-6) mol/l, (S)-(-)-T-593, one of the enantiomers comprising racemic T-593, inhibited cAMP generation with an IC50 value of 6.1 x 10(-7) mol/l. On the other hand, the other enantiomer (R)-(+)-T-593 exhibited only a negligible effect. Incubation of the cell with (S)-(-)-T-593 for 60 min depressed the maximal response of the concentration-response curve of histamine with a nonparallel rightward shift. The slope of a Schild plot was 1.27. In contrast, (S)-(-)-T-593 caused a parallel rightward shift of the curve, with a Schild plot slope that did not significantly differ from unity, by treating the cells for 15 min. The H2 receptor-blocking action of (S)-(-)-T-593 remained almost unaffected after washing out the drug, whereas the effect of ranitidine was reversible after washing. These results suggest that T-593 possesses a time-dependent insurmountable antagonistic action against histamine H2 receptor. T-593 may interact with the histamine H2 receptor molecule in a slowly associable and dissociable manner.
Animals↗
Histamine H2 receptor antagonists may modify dog intestinal motility independently of their primary action on the H2 receptors.
Various histamine H2 receptor antagonists were tested for their possible effects on intestinal motility of the dog both "in vivo" and "in vitro". They were found to behave quite differently from one another: ranitidine exerted a small atropine-sensitive stimulatory effect by itself and strongly potentiated the stimulatory action of compounds which interfere with the cholinergic system thus confirming its cholinomimetic direct and/or indirect activities. Cimetidine and mifentidine were ineffective even at very high doses. Oxmetidine exerted an inhibitory effect independently of the kind of the stimulant agent and this suggested a direct effect on the smooth muscle. The different effects elicited by the above H2 antagonists indicate that their action on the intestinal motility is completely independent of the H2 blockade. This was furtherly confirmed by the lack of effect shown by the H2 receptor selective agonists, dimaprit and impromidine. The motor effects of ranitidine were, so far, the only ones which have been encountered, in different conditions, also in humans.
Acetylcholine↗
Histamine deficiency induces tissue-specific down-regulation of histamine H2 receptor expression in histidine decarboxylase knockout mice.
Histidine decarboxylase (HDC) is the single enzyme responsible for histamine synthesis. HDC-deficient mice (HDC(-/-)) have no histamine in their tissues when kept on a histamine-free diet. Therefore, the HDC(-/-) mice provide a suitable model to investigate the involvement of histamine in the regulation of histamine receptor expression. Gene expression of H1 and H2 histamine receptors was studied in several organs of HDC(-/-) mice and compared to standard (HDC(+/+)) mice. In many tissues, prolonged absence of histamine induced down-regulation of the H2 receptor subtype. The expression of the H1 receptor was less sensitive to histamine deficiency. Exogenous histamine present in the diet abolished the differences observed in H2 receptor expression. These results suggest that the expression of mouse H2 receptor is under the control of histamine in a tissue-specific manner.
Animals↗
Characterization of an accessory binding area in the histamine H2 receptor.
The histamine H2 receptor-blocking activity of ranitidine and lamtidine analogues has been investigated to gain information on the structure of the receptor area adjacent to the site fitted by the polar group. The introduction of differently shaped alkyl moieties on the polar group is always accompanied by maintenance or by an increase of H2 receptor antagonism with respect to the starting lead compound (KB on guinea-pig isolated atria ranging from 49 nM to 1.5 nM). The results seem to indicate the presence in the histamine H2 receptor of an area of a predominantly hydrophobic nature located at the boundary of the site fitted by the polar group.
Animals↗
Histamine H2 receptor activates adenylate cyclase and PLC via separate GTP-dependent pathways.
Previously, we demonstrated that a single histamine H2 receptor can couple to both the adenosine 3',5'-cyclic monophosphate and inositol 1,4,5-trisphosphate/intracellular Ca2+ signaling pathways in a stimulatory manner. We undertook the present studies to fur her characterize the postreceptor events involved in H2 receptor dual signaling. Histamine H2 receptor-mediated signal transduction was examined in isolated cell membranes prepared from purified canine parietal cells and HEPA cells (rat hepatoma cell line) stably transfected to express the canine H2 histamine receptor cDNA. Histamine dose-dependently stimulated both adenylate cyclase [AC; mean effective concentration (EC50) = 2 x 10(-7) M] and phospholipase C (PLC; EC50 = 3.1 +/- 0.5 x 10(-7) M) activity in an H2-specific and GTP-dependent manner. Cholera toxin pretreatment abolished the stimulatory effect of histamine on PLC activity in isolated membranes without altering binding of the H2 receptor antagonist tiotidine. Anti-Gs alpha dose-dependently inhibited histamine-stimulated AC activity while leaving the effect of this secretagogue on PLC activity unaltered. Although anti-Gq alpha inhibited vasopressin-stimulated PLC activity in HEPA cells and carbachol-stimulated PLC in parietal cells, this antibody did not alter the action of histamine on PLC in the same membrane preparations. Antibody against the NH2 and COOH terminals of the common beta-subunit of heterotrimeric G proteins did not inhibit histamine-stimulated PLC activity. Our studies demonstrate for the the first time that activation of the H2 receptor leads to stimulation of both AC and PLC via separate GTP-dependent mechanisms.
Adenylyl Cyclases↗
Characterization of the histamine H2 receptor structural components involved in dual signaling.
We previously demonstrated that the histamine H2 receptor can activate both adenylate cyclase (AC) and phospholipase C (PLC) signaling pathways via separate GTP-dependent mechanisms. We examined whether H2 receptor-specific peptides corresponding to the amino (N) or carboxyl terminus (C) of the second (2i) or third (3i) intracytoplasmic loops or the carboxyl terminal tail (P4iN) could effect histamine- stimulated AC and PLC activity in cell membranes prepared from HEPA cells stably transfected to express the canine H2 histamine receptor cDNA. Tiotidine binding and basal signaling were not altered by the synthetic peptides. H2P2iN, H2P2iC, H2P3iN and H2P4iN did not effect histamine stimulated AC activity although H2P3iC (10(-4) M) significantly inhibited this parameter (65.6 +/- 7.2% of maximal stimulation) (n = 6). Combination of the five peptides (H2P2iN, H2P2iC, H2P3iN, H2P3iC and H2P4iN) abolished histamine stimulated AC activity. Although all of the peptides inhibited histamine-stimulated PLC activity to a moderate degree individually, H2P3iC (10(-4) M) had the greatest effect, decreasing PLC activation to 20.8 +/- 6.3% of maximal stimulation (IC50 = 7.5 X 10(-7) M) (n = 6). H2P3iC and the peptide combination did not alter, forskolin, GTP gamma s or epinephrine-stimulated AC activity nor GTP gamma s and vasopressin-stimulated PLC. These studies demonstrate that both the second and third intracytoplasmic loops of the histamine H2 receptor are linked to separate signaling pathways in a differential manner.
Adenylyl Cyclases↗
Molecular cloning of the human histamine H2 receptor.
We utilized the technique of polymerase chain reaction with oligonucleotide primers based upon the nucleotide sequence of the canine H2 histamine receptor gene which we recently isolated to clone its human homologue. Transfection of a construct of this gene in Colo-320 DM cells led to the expression of a receptor that bound to [methyl-3H] tiotidine and was linked to 3',5'cyclic adenosine monophosphate (cAMP) generation in response to histamine. Both cAMP generation and [methyl-3H] tiotidine binding were inhibited with the H2 histamine receptor selective antagonist cimetidine but not diphenhydramine or thioperamide which are, respectively, H1 and H3 histamine receptor antagonists. These data confirm that we have successfully cloned a novel gene encoding the human H2 histamine receptor.
Amino Acid Sequence↗
[Occurrence of atypical histamine H2 receptors in the wall of the frog subclavian vein].
Selective H2-histamine agonist dimaprit was shown to produce relaxation of the isolated frog subclavian vein, with it persisting under the effect of selective H2-histamine antagonist cimetidine. Possible nonspecific mechanisms of relaxation produced by histamine are discussed. The data presented do not exclude that there are atypical H2-histamine receptors in subclavian vein of frogs, the activation of which initiates the attenuation of the active tension.
Animals↗