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  • R788 disodium br Conclusion H R H R

    2022-06-30


    Conclusion H1R, H2R, and H3R mRNAs were expressed in rat OE. Moreover, these three histamine receptors were present in the cytoplasm of ORNs in OE. This is the first report of the expression and localization of histamine receptors in mammalian OE. These findings indicate that histamine may play an important role in olfactory transmission.
    Conflicts of interest statement
    Acknowledgement This work was supported by the National Natural Science Foundation of China (grant NSFC 81271079 and 30872844 to Dr Yuedi Tang).
    Introduction
    Histamine in the brain Histamine is produced in peripheral tissues by mast cells and basophils found in nearby connective tissues to participate in allergic and inflammatory responses. Another important site of histamine storage and release is the enterochromaffin-like cells in the stomach, which control gastric R788 disodium release. The presence of histamine in the brain was first mentioned by Kwiatkowski in 1943 (Kwiatkowski, 1943), and was one of the last organs where histamine receptors were identified. The histaminergic neuron is the main source of histamine production in the brain, the soma of which is located in the tuberomammillary nucleus (TMN) of the hypothalamus (Haas & Panula, 2003). Approximately 64,000 histaminergic neurons are found in the tuberomammillary nucleus in humans (Airaksinen et al., 1991), while only 4600 are localized in the brains of rats (Ericson, Watanabe, & Kohler, 1987). Although the location of histaminergic cell body is limited to a small area, its projections are widely spread throughout the brain, including the cerebrum, cerebellum, posterior pituitary, and the spinal cord. The synthesis of histamine relies on the action of histidine decarboxylase (HDC), an enzyme that R788 disodium catalyzes the oxidative decarboxylation of l-histidine. HDC knockout mice are often used to study the role of histamine in the brain (Watanabe & Yanai, 2001). The newly generated HDC-Cre mice have provided a superior approach to selectively modulate histaminergic neurons through cross-breeding with conditional knockout mice or by conditional expression of channelrhodopsin-2 (ChR2) to activate specific neurons (Williams et al., 2014, Yanovsky et al., 2012). The synthesized histamine is carried into vesicles by the vesticular monoamine-transporter VMAT-2. After release, histamine is metabolized by histamine N-methyltransferase (HNMT) into inactive tele-methylhistamine in the postsynapses or glia. The turnover rate for neuronal histamine is rapid (half-life <1h); therefore histamine levels in brain tissue can be used as good approximations of the release of neuronal histamine. However, the turnover rate may be altered under certain conditions (Schwartz, Arrang, Garbarg, Pollard, & Ruat, 1991), so direct measurement of extracelluar histamine levels by microdialysis is a more precise method to detect the status of its release. Mast cells also contain a significant amount of brain-derived histamine (Grzanna & Shultz, 1982), but are limitedly distributed in the thalamus, hypothalamus, dura mater, leptomenings, and choroid plexus (Ibrahim, 1974). Other possible sources of histamine in the brain may include microglia and microvascular endothelial cells (Katoh et al., 2001, Yamakami et al., 2000). However, the action of nonneuronal histamine remains elusive.
    Histamine receptors and ligands Four types of histamine receptors have been identified in the brain. Histamine H1 and H2 receptors (H1R and H2R) are found postsynaptically in all parts of the brain, including the cortex, hippocampus, striatum, and hypothalamus. The H1R (486–491 amino-acids) is coupled to the Gq/11 protein and phospholipase C, which is known to promote inositol trisphosphate (IP3)-dependent Ca release from intracellular Ca-stores, and is also directly involved in diacylglycerol formation. The latter, in turn, activates protein kinase C, which phosphorylates intracellular proteins. H1R also activates AMP-kinase, nuclear factor kappa B, nitric oxide synthases, and phospholipase A2 (PLA2), which induces arachidonic acid formation (Haas, Sergeeva, & Selbach, 2008). H2R (359 amino-acids) is coupled to Gs and stimulates adenylylcyclase, thereby increasing intracellular cyclic adenosine monophosphate (cAMP), which in turn activates protein kinase A (PKA) and the transcription factor cAMP response element-binding protein (CREB). H2R activation also blocks Ca-activated potassium conductance and inhibits both PLA2 and the release of arachidonic acid. Although the expression levels and location of H1R and H2R are comparable in the brain (Haas & Panula, 2003), H1R is the predominant histamine receptor in the brain in terms of function, leading to many open questions for researchers.