Recent Advances in Molecular Pharmacology of the Histamine Systems: Immune Regulatory Roles of Histamine Produced by Leukocytes (original) (raw)
Related papers
Journal of Pharmacological Sciences, 2006
Histamine H 1 receptor (H1R) signaling is regulated by changing its expression level. Two mechanisms are involved in this regulation. One is down-regulation through receptor desensitization. Receptor phosphorylation seemed crucial because stimulation of the mutant H1R lacking five putative phosphorylation sites did not show down-regulation. The phosphorylation level of the mutant receptor was much smaller than that of the wild type ones by several protein kinases. The other is up-regulation through activation of receptor gene expression. Protein kinase C (PKC) signaling was suggested to be involved in this up-regulation. Regulation of H1R expression level was mediated not only through H1R but also autonomic nerve receptors. Stimulation of M 3 muscarinic receptors (M3R) induced both down-regulation and up-regulation of H1R. Down-regulation of M3R-mediated H1R seemed not to be mediated by PKC activation, although PKC activation induced H1R phosphorylation. Elevation of H1R expression was induced by the stimulation of M3Rs. PKC was suggested to be involved in this up-regulation. Stimulation of β 2 -adrenergic receptors induced H1R down-regulation through several mechanisms. One of them is enhanced receptor degradation after desensitization and another is suppression of receptor synthesis that includes the suppression of receptor gene expression and enhanced degradation of the receptor mRNA. Protein kinase A was suggested to be involved in enhanced degradation and the activation of the receptor gene expression. Elevation of both H1R expression and its mRNA was observed in nasal mucosa of nasal hypersensitivity allergy model rat after toluene diisocyanate provocation. These results suggest that activation of H1R gene expression plays an important patho-physiological role in allergy. Elevation of the mRNA was partially but significantly suppressed by antihistamines.
Journal of Pharmacological Sciences, 2007
Histamine is a major mediator in allergy acting mainly through the histamine H 1 receptor (H1R). Although H1R up-regulation has been suggested as an important step for induction of allergic symptoms, little is known about the regulation of H1R level. Here we report that the activation of H1R up-regulates H1R through augmentation of H1R mRNA expression in HeLa cells. Histamine stimulation significantly increased both H1R promoter activity and mRNA level without alteration in mRNA stability. H1R protein was also up-regulated by histamine. An H1R antagonist but not histamine H 2 receptor antagonist blocked histamine-induced up-regulation of both promoter activity and mRNA expression. A protein kinase C (PKC) activator, phorbol-12-myristate-13-acetate, increased H1R mRNA expression, whereas an activator of PKA or PKG (8-Br-cAMP or 8-Br-cGMP, respectively) did not. Furthermore, histamine-induced upregulation of both promoter activity and mRNA level were completely suppressed by the PKC inhibitor Ro-31-8220. H1R antagonists have long been thought to block H1R and inhibit immediate allergy symptoms. In addition to this short-term effect, our data propose their longterm inhibitory effect against allergic diseases by suppressing PKC-mediated H1R gene transcription. This finding provides new insights into the therapeutic target of H1R antagonist in allergic diseases.
Journal of pharmacological sciences, 2016
Antihistamines inhibit histamine signaling by blocking histamine H1 receptor (H1R) or suppressing H1R signaling as inverse agonists. The H1R gene is upregulated in patients with pollinosis, and its expression level is correlated with the severity of nasal symptoms. Here, we show that antihistamine suppressed upregulation of histidine decarboxylase (HDC) mRNA expression in patients with pollinosis, and its expression level was correlated with that of H1R mRNA. Certain antihistamines, including mepyramine and diphenhydramine, suppress toluene-2,4-diisocyanate (TDI)-induced upregulation of HDC gene expression and increase HDC activity in TDI-sensitized rats. However, d-chlorpheniramine did not demonstrate any effect. The potencies of antihistamine suppressive effects on HDC mRNA elevation were different from their H1R receptor binding affinities. In TDI-sensitized rats, the potencies of antihistamine inhibitory effects on sneezing in the early phase were related to H1R binding. In cont...
British Journal of Pharmacology, 1992
In this study we have investigated the effects of short-term exposure of cells to histamine on the subsequent H, receptor responsiveness in HeLa cells, using Ca2+ fluorescence microscopy and video digital imaging. 2 In HeLa cells, histamine (100 1AM) induces an immediate HI receptor-mediated biphasic elevation of the intracellular Ca2+ concentration ([Ca2+],) (basal [Ca2+]i: 81 30 nM, histamine-induced Ca2`response: first phase: 1 135 + 79 nM; second phase: 601 ± 52 nM, n = 11). 3 The histamine H, receptors on HeLa cells are readily susceptible to desensitization since repetitive exposure of the same group of cells to histamine (100tIM) markedly affected the release and influx component of the induced Ca2+ response (second application of histamine: first phase: 590 + 92 nM, second phase: 279 ± 47 nM; third application of histamine: first phase: 454 ± 127 nM, second phase: 240 ± 45 nM, n = 6). Video digital imaging revealed an increase in the lag time between stimulation and monitoring of the Ca2+ response and a reduced increase in [Ca2+]i after desensitization with histamine. 4 Neither the release component of the ATP response (50 jiM) nor the caffeine (3 mM)-induced Ca2+ release were found to be affected by desensitization with 100 tIM histamine. However, the second phase of the ATP response was significantly reduced after desensitization with histamine (control cells: 516 ± 33 nM; desensitized cells: 331 + 96 nM, n = 4, P < 0.05). 5 Activation of protein kinase C (PKC) by phorbol-12-myristate-1 3-acetate was found to inhibit the histamine as well as ATP-induced Ca2" response in a dose-dependent manner. 6 In PKC downregulated cells the second phase of the histamine-induced Ca2+ response was significantly elevated, indicating the involvement of PKC in the negative feedback on the Ca2+ influx (control cells: second phase: 601 ± 52 nM (n = 11); PKC downregulated cells: second phase: 890 ± 90nM, n = I0, P<0.05). 7 Homologous desensitization of H, receptor responsiveness was still observed in PKC downregulated cells, implying the rapid activation of a regulatory mechanism other than PKC. 8 Based on our experimental data we suggest that short-term desensitization of the histamine H, receptor evolves from two different processes: a selective reduction of the histamine-induced Ca2+ release, mediated by a PKC-independent pathway, and a non-selective inhibition of the receptormediated Ca2+ influx activated by a PKC-dependent pathway.
Molecular and Functional Diversity of Histamine Receptor Subtypes
Annals of the New York Academy of Sciences, 1995
The early history of histamine is largcly associatcd with allcrgy. The major actions of histamine were described at the beginning of this century by Sir Henry Dale and his colleagues after its isolation from ergot extracts. Namely, its potcnt contractile cffccts on smooth muscles and thc capillary dilation it induces, which mimic some initial manifestations of the anaphylactic shock, were identified by these scientists. They also detccted the presence of the aminc in many tissues, but it was another British scientist, Feldberg, who clearly demonstrated that histamine was released from the lung during the anaphylactic response and that it induccd a marked bronchoconstriction.
Nature Reviews Drug Discovery, 2008
Histamine was first identified as a mediator of biological functions in the early 1900s and drugs targeting its recep tors have been in clinical use for more than 60 years. Histamine exerts a range of effects on many physiological and pathological processes and new roles are still being elucidated. The best characterized roles of histamine are those in inflammation, gastric acid secretion and as a neuro transmitter (FIG. 1). During inflammation, histamine is released from preformed stores in mast cells and basophils. Histamine acts on vascular smooth muscle cells and endothelial cells, leading to vasodilation and an increase in vascular permeability. In the skin, this results in the 'triple response' , which is an immediate local reddening due to vasodilation, a wheal due to increased vascular permea bility and a flare response due to indirect vasodilation via the stimulation of axonal reflexes 1. In the gastrointestinal system, histamine is essential for gastric acid secretion 2. Gastrin and vagal stimulation induce enterochromaffin like cells in the gut to release histamine. This histamine can then act on parietal cells to stimulate H + , K + ATPases, leading to the secretion of H + and subsequent acidifica tion that assists in digestive processes. Histamine is also a neurotransmitter in the CNS with a role in sleep-wake cycles, appetite, learning and memory 3. It is produced in a subset of neurons in the tuberomammillary nucleus of the hypothalamus and its effects are transmitted widely to other regions of the brain. These effects have led to the development of drug therapies for allergy, gastric ulcers, motion sickness and insomnia and have been so successful and widespread that the word antihistamine has entered the common lexi con. However, histamine has also been postulated to be involved in other conditions. For example, histamine is increased in bronchoalveolar lavage fluid from patients with allergic asthma and this increase negatively corre lates with airway function 4-9. An increase in histamine levels has been noted in the skin and plasma of patients with atopic dermatitis 10,11 and in chronic urticaria 12,13. Histamine levels are also increased in multiple sclerosis 14 and in psoriatic skin 15. Both plasma and synovial fluid of patients with rheumatoid arthritis and plasma of patients with psoriatic arthritis have increased hista mine levels 16,17. For all of these conditions, the traditional antihistamines are generally regarded to be ineffective, leading to the conclusion that histamine is not involved in their pathology. However, it is now known that the diverse biological effects of histamine are mediated through four different histamine receptors, including the most recently described histamine H 4 receptor. The antihistamines that are currently used in the clinic have little, if any, affinity for the H 4 receptor and, as outlined in this Review, this receptor has been shown to func tion in inflammatory responses in vitro and in vivo. This emerging role for the H 4 receptor and recent data on
Journal of Biological Chemistry, 1997
To evaluate the role of the histamine H2 receptor C terminus in signaling, desensitization, and agonist-induced internalization, canine H2 receptors with truncated C termini were generated. Wild-type (WT) and truncated receptors were tagged at their N termini with a hemagglutinin (HA) epitope and expressed in COS7 cells. Most of the C-terminal intracellular tail could be truncated (51 of 70 residues, termed T 308 mutant) without loss of functions: cAMP production, tiotidine binding, and plasma membrane targeting. In fact, the T 308 mutant produced more cAMP than the WT when cellsurface expression per cell was equivalent. Pretreatment of cells with 10 ؊5 M histamine desensitized cAMP productions via WT and T 308 receptors to similar extents. Incubation of cells expressing WT receptors with 10 ؊5 M histamine reduced cell-surface anti-HA antibody binding by approximately 30% (by 30 min, t 1/2 ϳ 15 min), but did not affect the B max of tiotidine in membrane fractions, which represents total receptor amounts, suggesting that WT receptors were internalized from the cell surface. In contrast, no internalization was observed with T 308 receptors following histamine treatment. A mutant with a deletion of the 30 C-terminal amino acids, termed T 329 , was functional but was as potent as the WT in terms of cAMP production. Apart from being desensitized by histamine, the internalization of the receptor was indistinguishable from that of the WT. Internalization was observed in the T 320 but not in T 313 mutant, narrowing the region involved in internalization to that between Glu 314 and Asn 320 (ETSLRSN). Of these seven residues, either Thr 315 , Ser 316 , or both, were replaced with Ala. Thr 315 and Ser 316 are conserved among species. The mutation at Thr 315 (but not that at Ser 316) abolished internalization. Taken together, these results demonstrate that Thr 315 is involved in agonistinduced internalization. Furthermore, the finding that T 308 receptors were desensitized in the absence of internalization suggests that internalization and desensitization are meditated by independent mechanisms.
New Developments in the Use of Histamine and Histamine Receptors
Current Allergy and Asthma Reports, 2010
Histamine and the histamine receptors are important regulators of a plethora of biological processes, including immediate hypersensitivity reactions and acid secretion in the stomach. In these roles, antihistamines have found widespread therapeutic applications, while the last receptor to be discovered, the H4 histamine receptor, has become a major target of novel therapeutics. Recent studies involving human genetic variance and the development of mice lacking specific receptors or the ability to generate histamine have shown roles for the histamine pathway that extend well beyond the established roles. These include identification of previously unappreciated mechanisms through which histamine regulates inflammation in allergy, as well as roles in autoimmunity, infection, and pain. As a result, antihistamines may have wider applications in the future than previously predicted.