Histamine signaling pathways

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. 

FIGURE 18.4 Pharmacologist s view of emetic stimuli. Myriad signaling pathways lead from the periphery to the emetic center. Stimulants of these pathways are noted in italics. These pathways involve specific neurotransmitters and their receptors (bold text). Receptors are shown for dopamine, D acetylcholine (muscarinic), M histamine, H and 5-hydroxytryptamine, 5-HT. Some of these receptor types also may mediate signaling in the emetic center. This knowledge offers a rationale for current antiemetic therapy. 

IL-5 is produced primarily by activated CD4+ T-cells (436,437), and in lower levels by eosinophils (438), mast cells (439, 440), basophils, B-cells, NK cells (441,442), and endothelial cells (443). The expression of IL-5 is predominantly regulated at the transcriptional level (444), and can be induced by a variety cf stimulants, usually through activation of the T-cell receptor and a second signaling pathway. IL-la and PMA can induce IL-5 expression histamine can also increase the production of IL-5 in activated T-cells (445). 

Janssen, L.J. and Sims, S.M. (1993) Histamine activates O and K currents in guinea-pig tracheal myocytes convergence with muscarinic signalling pathway. Journal of Physiology (London), 465 661-677. 

Whereas Hi receptors are involved with positive effects, H2 receptors appear to mainly mediate suppressive activities of histamine including gastric acid secretion, heart contraction, cell proliferation, differentiation, and some effects on the immune response. H2 receptors are coupled to the adenylate cyclase as well as the phosphoinositide second messenger systems via separate GTP-dependent mechanisms, but H2-dependent effects, particularly those of the central nervous system, are predominantly mediated through cAMP. It has been shown that receptor binding stimulates activation of c-Fos, c-Jun, PKC, and P70S6 kinase. Alternative signaling pathways have been reported (Fig. 3.7). These include a receptor-mediated increase in intracellular Ca and/or IP3 levels in HL-60 human promyelocytic leukemia cells and an increase in cAMP and inhibition of release of arachidonic acid in Chinese hamster ovary (CHO) cells transfected with rat cDNA and induced by calcium ionophore. 

Table 3.1 Summarized comparison of function, G protein coupling and signaling pathways of histamine H, H2, H3, and H4 receptors ...

Summarized comparisons of functions, indications for antagonists, G protein couphng, and signaling pathways for the four histamine receptors are shown in Table 3.1 and Fig. 3.7. 

Further elucidation of drug receptor (histamine, leukotriene, PAF, etc.)-activated signaling pathways. 

The cascade of the second messenger system for histamine release in the ECL cell has not been characterized. Isolated ECL cells studied in a perfusion chamber exhibit a biphasic increase in intracellular calcium when exposed to gastrin or PACAP. An early transient, presumably due to the release of calcium from intracellular stores, is followed by a steady-state increment due to caldum entry. Blockade of caldum entry by La blocks histamine release. It is likely that the increase in cell calcium causes the activation of a variety of calcium-dependent signaling pathways, including protein kinase C. The C kinase activator, the phorbol ester tetradecanoyl-13-phorbol acetate (TPA) stimulates histamine release, supporting the proposal that this protein kinase is a component of the calcium-dependent histamine-stimulation pathway. Because forskolin (an intracellular stimulant of adenylate cyclase) is also a potent agonist of histamine release, a role for cAAAP in histamine secretion is likely. This proposal is supported by increased cAMP levels in forskolin-stimulated ECL cells. 

Most GPCRs interact with and activate more than one G-protein subfamily, e.g., with Gs plus Gq/n (histamine H2, parathyroid hormone and calcitonin recqrtors), Gs plus G (luteinising hormone receptor, 32-adrenoceptor) or Gq/11 plus G12/13 (thromboxane A2, angiotensin ATb endothelin ETA receptors). Some receptors show even broader G-protein coupling, e.g., to Gi, Gq/n plus Gi n ( protease-activated receptors, lysophosphatidate and sphingosine-1-phosphate receptors) or even to all four G-protein subfamilies (thyrotropin receptor). This multiple coupling results in multiple signaling via different pathways and in a concerted reaction of the cell to the stimulus. 

Leurs, R., Traiffort, E., Arrang, J. M. et al. (1994). Guinea pig histamine HI receptor. II. Stable expression in Chinese hamster ovary cells reveals the interaction with three major signal transduction pathways. J. Neurochem. 62, 519-27. 

Presynaptic H3 receptors also are uniform in their signal transduction. They couple to Gi/o proteins and decrease the depolarization-induced release of neurotransmitters by inhibiting multiple calcium channels (e.g., Arrang et al. 1985 Schlicker et al. 1994 Endou et al. 1994 Brown and Haas 1999 see Stark et al. 2004). For comparison, the signal transduction of soma-dendritic H3 autoreceptors in histamin-ergic neurons also involves a pertussis toxin-sensitive G-protein with subsequent inhibition of N- and P-type Ca2+ channels (Takeshita et al. 1998). The few exceptions to this signal transduction pathway are discussed in the corresponding subsections below (see Sections 3.1, 3.3, and 3.9). 

H3 receptor activation attenuates the release of glutmate in several brain regions (Table 3), but an endogenous input to the receptors has not been demonstrated. In the dentate gyrus adenosine, acting at Ai receptors, also attenuated the release of glutamate and occluded further inhibition by histamine, presumably because a common signal transduction pathway (Brown and Haas 1999). 

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