Histamine release calcium dependence

Histamine is stored within and released from neurons but a neuronal transporter for histamine has not been found. Newly synthesized neuronal histamine is transported into TM neuronal vesicles by the vesicular monoamine transporter VMAT2 [16]. Both in vivo and in vitro studies show that depolarization of nerve terminals activates the exocytotic release of histamine by a voltage- and calcium-dependent mechanism. Once released, histamine activates both postsynaptic and presynaptic receptors. Unlike the nerve terminals from other amine transmitters, however, histaminergic nerve terminals do not exhibit a high-affinity uptake system for histamine [5, 9, 23]. Astrocytes may contain a histamine transport system. 

NT was initially reported to stimulate the non-cytotoxic release of histamine from isolated rat peritoneal mast cells by workers in our laboratory [40, 79]. This observation has now been confirmed and extended by several other workers [80-85]. When added to isolated rat serosal mast cells, NT initiates the secretion of histamine which is dependent upon calcium and energy [79]. Secretion begins at about 10 nanomolar NT and reaches an initial plateau of some 20% histamine release at 10 piM NT [79] (Figure 4.2) while higher levels... 

The ability of SP to stimulate histamine release from isolated rat peritoneal mast cells is now well demonstrated [31, 97-101], The release is rapid (< 1 min), non-cytotoxic, dependent on a supply of Ca and metabolic energy, and independent of cell-bound IgE [99]. Moreover, as with other peptides, its secretory effect on the mast cell is affected by moderate levels of extracellular cations. For example, the addition of Ca to the bathing medium after the addition of SP increased the secretory response of the cells, while adding calcium (0.1-1 mM), magnesium (1-10 mM) or cobalt (0.01-1 mM) to the cell suspension before SP inhibited histamine release, suggesting the possibility of cation competition for SP binding [99]. 

Robinson, C., Benyon, R.C., Holgate, S.T. and Church, M.K. (1989) The IgE- and calcium-dependent release of eicosanoids and histamine from human cutaneous mast cells. J. Invest. Dermatol. 93, 397-404. 

The histamine release in the brain, and perhaps other sites, involves exocytosis, as this potassium-induced release is a calcium-dependent process. Histamine is released by many factors. For example, histamine is released by numer-ons drugs including reserpine, codeine, meperidine, hydralazine, morphine, d-tnbocurarine, dextrans, papaverine, and compound 48/80. However, the different histamine storage sites show certain degrees of specificity. For example, the histamine in mast cells is not released following potassium-induced depolarization or by reserpine, factors that release histamine from nenrons. Conversely, compound 48/80, which releases histamine from mast cells, is not able to release histamine from nenrons. 

Like other nenrotransmitters, newly synthesized neuronal histamine is stored within the nerve terminal vesicle. Depolarization of nerve terminals activates the exocytotic release of histamine by voltage-dependent as well as a calcium-dependent mechanism. 

Experiments were carried out to see if suxamethonium-induced histamine release in the susceptible individuals was calcium dependent. Figure 5 shows that in the absence of calcium histamine release by suxamethonium was completely inhibited. Had it not been the case, one would have been certain that the reaction was not immunologically mediated. Thus, the calcium dependence of histamine release with suxamethonium in this patient was inconclusive, i.e., it did not contribute much to the further analysis of the mechanism, as to whether suxamethonium acts as an allergen or as a histamine releaser. 

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. 

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. 

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