Histamine Phospholipase

TBT and TFT are membrane-active molecules, and their mechanism of action appears to be strongly dependent on organotin(IV) lipophilicity. They function as ionophores and produce hemolysis, release Ca(II) from sarcoplasmic reticulum, alter phosphatodylseiine-induced histamine release, alter mitochondrial membrane permeability and perturb membrane enzymes. Organotin(IV) compounds have been shown to affect cell signaling they activate protein kinase and increase free arachidonic acid through the activation of phospholipase... 

Schaefer U, Schneider A, Rixen D, Neugebauer E (1998) Neutrophil adhesion to histamine stimulated cultured endothelial cells is primarily mediated via activation of phospholipase C and nitric oxide synthase isozymes. Inflamm Res 47(6) 256-264 Schaefer U, Schmitz V, Schneider A, Neugebauer E (1999) Histamine induced homologous and heterologous regulation of histamine receptor subtype mRNA expression in cultured endothelial ceUs. Shock 12(4) 309-315... 

Histamine Hi, Hj Hz G, Gs Phospholipase-C to IPzto [Ca +]i regulation Stimulates adenylyl cyclase raising cAMP... 

The characteristics of the four major classes of histamine receptors are summarized. Question marks indicate suggestions from the literature that have not been confirmed. AA, arachidonic acid DAG, diacylglycerol Iko,2+, calcium-activated potassium current IP3, inositol 1,4,5-trisphosphate NHE, sodium-proton exchange, PKC, protein kinase C NO, nitric oxide PTPLC, phosphoinositide-specific phospholipase C TXA2, thromboxane A2. Has brain-penetrating characteristics after systemic administration. 

FIGURE 14-6 Main signaling pathways for histamine receptors. Histamine can couple to a variety of G-protein-linked signal transduction pathways via its four different receptors. The Hj receptor activates the phosphatidylinositol turnover via Gq/11 proteins. The other receptors either positively (H2 receptor) or negatively (H3 and H4 receptor) regulate adenylyl cyclase activity via Gs and GUo protein activation respectively. Several additional signaling pathways have been described, which are not shown. Abbreviations PfP2, phosphatidylinositol 4,5-bisphosphate PIC, phospholipase C AC, adenylyl cyclase ATP, adenosine triphosphate cAMP, cyclic AMP PKC, protein kinase C PICA, protein kinase A. 

Histamine Hi receptor Nerve cells, airway and vascular smooth muscles, hepatocytes, chondrocytes, endothelial cells, epithelial cells, neutrophils, eosinophils, monocytes, DC,T and B cells Ca +, cGMP, phospholipase D, phospholipase Aj, NF-kB Gq/n... 

Glucocorticosteroids are the most potent antiinflammatory agents available. They stabilize lysosomal membranes and reduce the concentration of proteolytic enzymes at the site of inflammation. They promote the synthesis of proteins called lipocortins which inhibit phospholipase-A2 and thus inhibit production of arachidonic acid, leukotrienes and prostaglandins. Furthermore, the expression of COX-II and through that the inflammatory effects of the licosanoids is inhibited. Glucocorticosteroids reduce the release of histamine from basophils, decrease capillary permeability and cause vasoconstriction. Glucocorticosteroids stimulate the loss of calcium with the urine and inhibit the resorption of calcium from the gut. 

Drugs, particularly organic bases, may release histamine from mast cells by physically displacing the amine from its storage sites. Morphine, codeine, d-tubocu-rarine, guanethidine, and radiocontrast media can release histamine from mast cells. Basic polypeptides, such as bradykinin, neurotensin, substance P, somatostatin, polymyxin B, and the anaphylatoxins resulting from complement activation, also stimulate histamine release. Venoms often contain basic polypeptides as well as the histamine-releasing enzyme phospholipase A. 

Hi Phospholipase C-mediated Ca++ mohilization Brain, smooth muscle, heart, endothelium 2-(3-trifluoromethyl) phenyl histamine Mepyramine, chlorpheniramine, triplodine... 

The biological effects of histamine (Table 15.1) are mediated via three receptor subtypes, HI, H2 and H3 that are linked to G protein but activate different cell-signalling systems. The histamine HI receptor is associated with the phospholipase C-catalysed formation of inositol 1,4,5-triphosphate (IP3) and 1,2-diacylglycerol (DAG). The H2-receptor is coupled to adenylyl cyclase, increasing the production of cAMP. The cellular messenger system involved in H3-receptor activation has not been fully defined, but it may couple to N-type Ca2+-channels. The genes encoding for HI and H2 receptors have been cloned. A mutation of the human H2 receptor has been linked to schizophrenia. 

Stimulated platelets release arachidonic acid rapidly from their phospholipids, apparently as a result of activation of phospholipase A2. The released arachidonate can in turn be metabolized to endoperoxides and thromboxane A2 (Chapter 21). These compounds are also potent activators of platelets and cause a self-activating or autocrine effect.1) While PAF has a beneficial function, it can under some conditions contribute in a dangerous way to inflammation and to allergic responses including anaphylaxis,) asthmag and cold-induced urticaria.1 Although the effect of PAF is separate from those of histamine and of leukotrienes, these agents may act cooperatively to induce inflammation.1... 

Increased levels of myeloperoxidase and phospholipase Increased levels of histamine, 5-HT, leukotrienes, prostaglandins... 

Scorpionid secretions represent a mixture of neurotoxic polypeptide toxins, proteolytic and hemolytic enzymes (phospholipases A, acetylcholinesterases, ribonucleases, hyaluronidases), and biogenic amines (serotonin, tryptamine, histamine). The polypeptide toxins (the so-called scorpamines) contain fewer than 40 or 60-76 mostly alkaline and aromatic amino acids stabilized by four disulfide bridges.20 96... 

Oprins, J.C., Van der Burg, C., Meijer, H.P., Munnik, T. and Groot, J.A., 2002, Tumor necrosis factor alpha potentiates ion secretion induced by histamine in a human intestinal epithelial cell line and in mouse colon involvement of the phospholipase D pathway. Gut 50 314—321. 

Forster E, Dudler T, Gmachl M, Aberer W, Utbanek R, Suter M Natural and recombinant enzymatically active or inactive bee venom phospholipase A2 has the same potency to release histamine from basophils in patients with hymenoptera allergy. J Allergy Clin Immunol 1995 95 1229-1235. 

Evidence indicates that steroids affect other cells and substances that modulate inflammation. Exposure of human basophils to steroid in culture inhibits histamine release induced by an IgE-dependent stimulus. Steroids inhibit phospholipase A2, which prevents biosynthesis of arachidonic acid and subsequent formation of prostacyclin, thromboxane A, prostaglandins, and leukotrienes. Steroids also decrease capillary permeability and fibroblast proliferation and the quantity of collagen deposition, thereby influencing tissue regeneration and repair. 

Concerning mediators of immediate hypersensitivity, the most important include histamine, leukotriene e.g., SRS-A (slow-reacting substance of anaphylaxis, ECF-A (eosinophil chemotactic factor of anaphylaxis), PAF (platelet-activating factor), and serotonin. There are also three classes of lipid mediators that are synthesized by activated mast cells through reactions initiated by the actions of phospholipase A2. These are prostaglandins, leukotrienes, and platelet-activating factors (PAF). 

Histamine released from mast cells plays an important physiological role in immediate hypersensitivity and allergic responses. In addition, histamine functions as a neurotransmitter in the CNS and it is a potent stimulus for gastric acid secretion. These actions depend on the interaction of histamine with two types of receptors, Hi and H2. Hi and H2 receptors are coupled via G proteins to phospholipase C and adenylyl cyclase, respectively. The principal H3 receptor response is stimulation of gastric acid secretion, whereas other actions of histamine (e.g., smooth muscle contraction, vasodilation, increased capillary permeability, pain, and itching) are prunarily mediated by Hi receptors. 

Figure 2.13. Histamine H,-receptor-mediated inositol phospholipid hydrolysis. Stimulation of H,-receptors leads to activation of a phospholipase C. probably via a guanine-nucleotide regulatory protein (N). which catalyses the hydrolysis of phosphatidylinositol 4.5 -bisphosphate (PIP2) to give inositol trisphosphate (IP3) and 1,2-diacylglycerol (DG). IP3 is then broken down by phosphatases to eventually yield free myo-inositol. Lithium ions can inhibit the conversion of inositol 1-phosphate (IP,) to myo-inositol. Free inositol then interacts with CDP-diacylglycerol,formed by a reaction between phosphatidic acid (PA) and CTP, to yield phosphatidylinositol (PI). Phosphorylation of PI by kinases completes the lipid cycle by reforming PIP2. Modified from [147,148].

Studies in slices of rat cerebral cortex have shown that the accumulation of [3H]inositol 1-phosphate elicited by histamine can be abolished by omission of calcium from the incubation medium [240]. This is not the result that would be expected if inositol phosphate were generated solely by the pathway outlined in Figure 2.13 and does not support the hypothesis that phospholipase-C-mediated inositol phosphate production precedes, rather than results from, Ca2 + mobilization. However, interpretation of this finding is complicated by the effect of calcium ion removal on the incorporation of [3H]inositol into the... 

Triterpenes are widely distributed in plants, and in many cases are the principles responsible for their anti-inflammatory effects. Many of these compounds are active in different in vivo experimental models such as hind paw edema induced by carrageenan, serotonin and phospholipase A2 ear edema induced by phorbol and daphnane esters, ethylphenylpropiolate, arachidonic acid and capsaicin adjuvant arthritis and experimental models of allergy. Other effects have been studied in vitro, and some triterpenes are active against inflammatory enzymes like 5-lipoxygenase, elastase and phospholipase A2. Others inhibit histamine, collagenase and interleukin release, lipid peroxidation and free radical-mediated processes, metabolism of endogenous corticoids, and complement and protein-kinase activities. 

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