Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Actions of histamine on the voltage-dependent Ba2+(Ca2+) currents (IBa, ICa) were investigated using the whole-cell patch-clamp technique on dispersed smooth muscle cells from the rabbit saphenous artery. 2. Histamine (half-maximal dose, EC50 = 530 nM) augmented the IBa evoked by a brief depolarizing pulse (100 ms duration; to +10 mV from a holding potential of -80 mV) in a concentration-dependent manner. The maximum augmentation was obtained with 30 microM-histamine (1.29 times control). This augmentation of IBa was inhibited by the H3-antagonist, thioperamide (Ki = 30 nM, slope of the Schild plot = 1.0), but not by H1- or H2-antagonists (mepyramine or diphenhydramine, or cimetidine, respectively). 3. An H3-agonist, R alpha-methylhistamine (EC50 = 93 nM), also augmented IBa in a concentration-dependent manner at a holding potential of -80 mV and the maximum augmentation (1.25 times control) was obtained with 10 microM. This augmentation was also inhibited by thioperamide, but not by the above H1- and H2- antagonists. 4. Intracellularly applied 500 microM-guanosine 5'-triphosphate (GTP) enhanced, but 1 mM-guanosine 5'-O-(2-thiodiphosphate) (GDP beta S) abolished, the histamine-induced augmentation of IBa. When one of the non-hydrolysable GTP analogues, guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S; greater than 5 microM), guanylyl-imidodiphosphate (GMP-PNP; 200 microM) or guanylyl (beta, gamma-methylene)-diphosphonate (GMP-PCP; 1 mM) was intracellularly applied, the IBa amplitude evoked without the application of histamine was not affected, but the excitatory effect of histamine on IBa was reversed to an inhibition. Pre-treatment with pertussis toxin (PTX: 300 ng/ml and 3 micrograms/ml) did not modify the histamine-induced responses in the absence or presence of GTP gamma S. 5. 4 beta-Phorbol 12,13-dibutylate (PDBu) increased the amplitude of IBa. However, this action of PDBu was not enhanced by the application of GTP (500 microM) in the pipette, but additional application of histamine further increased the amplitude of IBa. Pre-treatment with a potent non-selective protein kinase inhibitor, 1-(5-isoquinolinesulphonyl)-2-methylpiperazine dihydrochloride (H-7; 100 microM), did not modify the histamine-induced current augmentation or inhibition observed in the presence or absence of intracellular GTP gamma S.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Histamine H3-receptor activation augments voltage-dependent Ca2+ current via GTP hydrolysis in rabbit saphenous artery. 131 41

The histamine H3 receptor agonist (R)alpha-methylhistamine (MeHA) inhibited, in a nanomolar range, basal and carbachol-stimulated inositol phosphate formation in the human gastric tumoral cell line HGT1-clone 6. The inhibition was reversed by micromolar concentrations of the histamine H3 receptor antagonist thioperamide and was sensitive to cholera or pertussis toxin treatment. Using [3H]N alpha-MeHA as specific tracer, high affinity binding sites were demonstrated with a Bmax of 54 +/- 3 fmol/mg of protein and a KD of either 0.61 +/- 0.04 or 2.2 +/- 0.4 nM, in the absence or presence of 50 microM GTP[gamma]S, respectively. The binding sites were solubilized by Triton X-100 and prepurified by gel chromatography. They were separated from the histamine H2 receptor sites by filtration through Sepharose-famotidine and finally retained on Sepharose-thioperamide. The purified sites concentrated in one single silver-stained protein band of 70 kDa in SDS-polyacrylamide gel electrophoresis. They specifically bound [3H]N alpha-MeHA with a KD of 1.6 +/- 0.1 nM and a Bmax of 12,000 +/- 750 pmol/mg of protein. This corresponds to a 90,225-fold purification over cell lysate and a purity degree of 84%. Binding was competitively displaced by N alpha-MeHA (IC50 = 5.8 +/- 0.7 nM), (R) alpha-MeHA (IC50 = 9 +/- 1 nM), and thioperamide (IC50 = 85 +/- 10 nM), but not by famotidine (H2 antagonist) or by mepyramine (H1 antagonist). These findings provide the first evidence for solubilization, purification, and molecular mass characterization of the histamine H3 receptor protein and for the negative coupling of this receptor phosphatidylinositol turnover through a so far unidentified G protein.
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PMID:Purification of a histamine H3 receptor negatively coupled to phosphoinositide turnover in the human gastric cell line HGT1. 133 91

1. The inhibitory effect of the histamine H3-receptor agonist (R) alpha-methylhistamine on cholinergic neurotransmission was studied in the isolated guinea pig duodenum in the presence of different compounds which alter intracellular levels of cyclic nucleotides and of the G proteins blocker pertussis toxin. 2. The action of (R) alpha-methylhistamine on electrically-evoked contractions was not modified either by forskolin and isobutylmethylxanthine (which increase cyclic AMP) or by zaprinast and methylene blue (which increase and decrease, respectively intracellular cyclic GMP). Drugs affecting cyclic nucleotide levels were also ineffective against the inhibitory effect of the alpha 2 adrenergic agonist clonidine. 3. Pertussis toxin significantly reduced the maximum inhibition induced by (R) alpha-methylhistamine and clonidine, without influencing the effect of low concentrations of the above compounds; conversely it shifted to the right in a parallel way the inhibitory effect of adenosine. 4. These data suggest that H3-receptor-mediated inhibition of cholinergic transmission in the guinea pig duodenum is not linked to intracellular nucleotide changes. Moreover the signal transducing mechanism activated by (R) alpha-methylhistamine involves pertussis toxin both sensitive and insensitive G proteins.
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PMID:Histamine H3-receptor-induced inhibition of duodenal cholinergic transmission is independent of intracellular cyclic AMP and GMP. 750 59

In dibutyryl cAMP-differentiated human leukemia (HL-60) cells, the potent histamine H1-receptor agonist, 2-(3-chlorophenyl)histamine, activates pertussis toxin (PTX)-sensitive guanine nucleotide-binding proteins (G-proteins) of the Gi-subfamily by a mechanism which is independent of known histamine receptor subtypes (Seifert et al. Mol Pharmacol 45: 578-586, 1994). In order to learn more about this G-protein activation, we studied the effects of histamine and various 2-substituted histamine derivatives in various cell types and on purified G-proteins. In HL-60 cells, histamine and 2-methylhistamine increased cytosolic Ca2+ concentration ([Ca2+]i) in a clemastine-sensitive manner. Phenyl- and thienyl-substituted histamines increased [Ca2+]i as well, but their effects were not inhibited by histamine receptor antagonists. 2-Substituted histamines activated high-affinity GTPase in HL-60 cell membranes in a PTX-sensitive manner, with the lipophilicity of substances increasing their effectiveness. Although HEL cells do not possess histamine receptors mediating rises in [Ca2+]i, 2-(3-bromophenyl)histamine increased [Ca2+]i in a PTX-sensitive manner. It also increased GTP hydrolysis by Gi-proteins in HEL cell membranes. All these stimulatory effects of 2-substituted histamine derivatives were seen at concentrations higher than those required for activation of H1-receptors. In various other cell types and membrane systems, 2-substituted histamine derivatives showed no or only weak stimulatory effects on G-proteins. 2-Substituted histamine derivatives activated GTP hydrolysis by purified bovine brain Gi/Go-proteins and by pure Gi2 (the major PTX-sensitive G-protein in HL-60 and HEL cells). Our data suggest the following: (1) histamine and 2-methylhistamine act as H1-receptor agonists in HL-60 cells; (2) incorporation of bulky and lipophilic groups results in loss of H1-agonistic activity of 2-substituted histamine derivatives in HL-60 cells but causes a receptor-independent G-protein-stimulatory activity; (3) the effects of 2-substituted histamine derivatives on G-proteins are cell-type specific.
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PMID:Histamine receptor-dependent and/or -independent activation of guanine nucleotide-binding proteins by histamine and 2-substituted histamine derivatives in human leukemia (HL-60) and human erythroleukemia (HEL) cells. 774 62

Presynaptic H3 receptors occur on histaminergic neurones of the CNS (autoreceptors) and on non-histaminergic neurones of the central and autonomic nervous system (heteroreceptors). H3 heteroreceptors, most probably located on the postganglionic sympathetic nerve fibres innervating the resistance vessels and the heart, have been identified in the model of the pithed rat. Furthermore, we could show in superfusion experiments that H3 heteroreceptors also occur on the sympathetic neurones supplying the human saphenous vein and the vasculature of the pig retina and on the serotoninergic, dopaminergic and noradrenergic neurones in the brain of various mammalian species, including man. The effects of three recently described H3 receptor ligands were studied in superfused mouse brain cortex slices. The potency of the novel H3 receptor agonist imetit exceeded that of R-(-)-alpha-methylhistamine (the reference H3 receptor agonist) by one log unit and that of histamine by almost two log units. Clobenpropit was shown to be a competitive H3 receptor antagonist, exhibiting a pA2 as high as 9.6 (exceeding the pA2 of the reference H3 receptor antagonist thioperamide by one log unit). The irreversible antagonism of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) was also studied. Interactions of the H3 heteroreceptor with the dopamine autoreceptor in mouse striatal slices and the alpha 2-autoreceptor in mouse brain cortex slices could be demonstrated. Activation of alpha 2-autoreceptors decreases the H3 receptor-mediated effect. Blockade of alpha 2-autoreceptors increases the H3 receptor-mediated effect only if the alpha 2-autoreceptors are simultaneously activated by endogenous noradrenaline. The H3 receptor-mediated inhibition of noradrenaline release in mouse brain cortex slices was attenuated by the K+ channel blocker tetraethylammonium but this attenuation was abolished by reduction of the Ca2+ concentration in the medium (to compensate for the facilitatory effect of tetraethylammonium on noradrenaline release). Accordingly, we assume that the H3 receptors are not coupled to voltage-sensitive K+ channels. Pertussis toxin and N-ethylmaleimide attenuated the H3 receptor-mediated effect in the mouse brain cortex, suggesting that the H3 receptors are coupled to a G protein (eg Gi or Go). However, negative coupling to an adenylate cyclase does not appear to exist since an H3 receptor-mediated inhibition of cAMP accumulation was not obtained in mouse brain cortex membranes. H3 receptor ligands are currently undergoing clinical testing and might become new remedies for the treatment of disease of the gastrointestinal and bronchial system and the CNS.
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PMID:Modulation of neurotransmitter release via histamine H3 heteroreceptors. 802 Aug 71

Agonist occupancy of high affinity histamine H3 receptors on AtT-20 cells induces increased ACTH release. However, the signal transduction process by which this occurs is presently unknown. As a first step in characterizing this pathway, we have examined the effects of a variety of nucleotides and nucleotide analogs on Na-methylhistamine binding to these receptors. Nonhydrolyzable guanine nucleotide analogs inhibit up to 40% of the [3H]Na-methylhistamine binding by increasing the dissociation rate of the ligand from the receptor and, thereby, reducing receptor affinity. Pertussis toxin also decreases the affinity of the H3 receptors and ADP ribosylates a 41 kDa protein. Neither GTP gamma S nor pertussis toxin change Bmax. These data indicate that the H3 receptors on these cells are coupled to a G protein of the Gi subclass.
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PMID:Guanine nucleotides and pertussis toxin reduce the affinity of histamine H3 receptors on AtT-20 cells. 802 37

Histamine H3 receptors have been identified in rat and guinea-pig pituitary glands and in the mouse pituitary tumor cell line, AtT-20. Histamine H3 receptor agonists are reported to stimulate adrenocorticotropic hormone (ACTH) release from AtT-20 cells, an effect blocked by histamine H3 but not H1 or H2 receptor antagonists. To determine whether negative feedback regulation of the histamine H3 receptor-mediated effect might occur, we tested the effects of steroid treatment upon binding of the agonist [3H]N alpha-methylhistamine to AtT-20 cell membranes. Consistent with feedback regulation, steroid treatment of the cells reduced [3H]N alpha-methylhistamine binding. The effect was dose-dependent and was greatest for glucocorticoids among the steroids tested. As the duration of steroid treatment increased, the amount of [3H]N alpha-methylhistamine binding decreased, to 15% of control at 36 h. However, the effect was not specific for histamine H3 receptors. Somatostatin inhibits ACTH release from these cells and its binding was similarly reduced by steroid treatment. Because steroids have been reported to modulate levels of guanine nucleotide-binding proteins, the lack of receptor specificity could reflect an indirect effect of steroids upon agonist binding and, in fact, we show that [3H]N alpha-methylhistamine binding to these cells, like somatostatin, is pertussis toxin-sensitive. However, steroid treatment does not alter the apparent levels of pertussis toxin substrate in these cells. Whether steroid treatment affects histamine H3 receptors of these cells directly or through some more subtle effect upon the guanine nucleotide-binding proteins to which they couple, the result is a negative feedback loop that attenuates [3H]N alpha-methylhistamine binding to these cells.
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PMID:Steroid-sensitivity of agonist binding to pituitary cell line histamine H3 receptors. 808 74

Discovered as inhibitory autoreceptors in central histaminergic pathways, histamine H3-receptors may also modulate peripheral cholinergic and central adrenergic function. Recently, H3-receptors were reported to inhibit adrenergic inotropic responses in guinea pig atria, possibly at prejunctional sites. We have assessed whether the H3-mediated modulation of cardiac adrenergic activities results from a reduction in norepinephrine release. We have found that (R) alpha-methylhistamine, the selective histamine H3-receptor agonist, attenuates the inotropic and chronotropic response of isolated guinea pig atria to transmural stimulation of adrenergic nerve endings. This attenuation was associated with a marked reduction in endogenous norepinephrine release. In contrast (R) alpha-methylhistamine did not modify the chronotropic effect of exogenous norepinephrine. The attenuation of adrenergic responses by (R) alpha-methylhistamine was 1) prevented by thioperamide, the selective H3-receptor antagonist; 2) attenuated by pertussis-toxin pretreatment and 3) potentiated by the N-type Ca(++)-channel blocker omega-conotoxin, which also potentiated the sympathetic modulatory effects of adrenergic-alpha 2 and adenosine-A1 receptor agonists. Our findings indicate that prejunctional histamine H3-receptors modulate the depolarization-dependent norepinephrine release from sympathetic nerve endings in the guinea pig myocardium. These receptors are probably coupled to a pertussis-toxin-sensitive Gi/Go protein and probably effect a reduction in Ca++ current. We have previously reported that sympathetic stimulation elicits a frequency-dependent release of cardiac histamine, whereas others had found that adrenergic activity regulates histamine's rapid turnover pool. Accordingly, presynaptic H3-receptors are likely to serve a modulatory role in cardiac adrenergic function.
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PMID:Histamine H3-receptor signaling in the heart: possible involvement of Gi/Go proteins and N-type Ca++ channels. 816 30

1. The effect of histamine H1-receptor stimulation on inositol phospholipid hydrolysis has been investigated in the hamster vas deferens smooth muscle cell line, DDT1MF-2. 2. Histamine (EC50 = 27 microM) stimulated the accumulation of [3H]-inositol phosphates in DDT1MF-2 cells prelabelled with [3H]-myo-inositol. 2-Thiazolylethylamine (EC50 42 microM) produced a maximal response of similar magnitude to histamine while the maximal response obtained with N alpha-methylhistamine (EC50 = 72 microM) and 2-pyridylethylamine (EC50 = 85 microM) were much lower (circa 65%, histamine = 100%). 3. The H1-selective agonists 2-(3-fluorophenyl)-histamine (2-FPH) and 2-(3-chlorophenyl)-histamine (2-CPH) both appeared to act as partial H1-agonists in this system. Both compounds produced maximal responses of only 30% (with respect to histamine = 100) and were able to antagonize the inositol phosphate response to histamine (estimated Kp = 10.4 and 18.9 microM for 2-FPH and 2-CPH respectively). 4. The response to histamine was antagonized by the H1-antagonists, mepyramine (KD 0.4 nM), (+)-chlorpheniramine (KD 1.2 nM) and promethazine (KD 0.3 nM). Furthermore, the (-)-isomer of chlorpheniramine was approx. three orders of magnitude less potent than the corresponding (+)-isomer. 5. The response to histamine (0.1 mM) was not altered by prior treatment of cells with pertussis toxin (100 ng ml-1; 24 h) whereas the inositol phosphate response to adenosine A1-receptor stimulation in this cell line was significantly attenuated under these conditions. 6. These data indicate that histamine-stimulated inositol phospholipid hydrolysis in DDT1MF-2 cells is mediated via a classical H1-receptor. Furthermore, the results also suggest that histamine HI- and adenosine A,-receptors activate phospholipase C in DDTMF-2 cells via two different G-protein-coupled pathways.
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PMID:Histamine H1-receptor-mediated inositol phospholipid hydrolysis in DDT1MF-2 cells: agonist and antagonist properties. 838 20

Rat spinal cord slices prelabelled with [3H]noradrenaline were superfused with a medium containing 1 mu M desipramine plus 0.3 mu M phentolamine. Histamine (0.01-10 mu M) and the selective histamine H3 receptor agonist R-(-)-alpha-methylhistamine (0.001-10 mu M) caused a concentration-dependent decrease in the release of radioactivity evoked by electrical field stimulation (0.8 Hz, 20 mA, 2 min). The inhibitory effect of histamine was not modified by either pyrilamine (1 mu M) or ranitidine (10 mu M), but it was antagonized by burimamide (1 mu M). The inhibitory action of histamine (1 mu M) was attenuated by pertussis toxin (3 mu g/ml) and was abolished by N-ethylmaleimide (30 mu M). Neither forskolin (10 mu M) nor rolipram (100 mu M), nor the combination of both drugs, modified the inhibitory effect of histamine. Histamine (1 mu M) did not modify the overflow of tritium induced by electrical stimulation in the absence of phentolamine. The present results suggest that in the rat spinal cord the release of noradrenaline elicited by electrical stimulation is negatively modulated by histamine, probably through the activation of histamine H3 receptors. This modulatory mechanism is likely to involve the participation of regulatory Go/Gi proteins.
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PMID:Possible participation of histamine H3 receptors in the modulation of noradrenaline release from rat spinal cord slices. 874 26


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