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  • This crosstalk may be responsible for the beneficial effects

    2021-12-02

    This crosstalk may be responsible for the beneficial effects of histamine H2 receptor inverse agonists on mma f pathologies and may also explain unwanted effects of these drugs on other tissues. In this way, Allen et al. reported an anaphylactoid reaction following cessation of high-dose ranitidine in a 19-year-old female with mast cell activation syndrome, hypermobile Ehlers-Danlos syndrome and postural tachycardia syndrome (Allen et al., 2018). The authors suggest that patients who take ranitidine, after withdrawal, can suffer an exacerbated effect of histamine caused by upregulation of histamine H2 receptor and raised histamine levels due to histidine decarboxylase induction, which is in concordance with previous in vitro studies (Alonso et al., 2015, Monczor and Fernandez, 2016, Smit et al., 1996). Considering our present results, it is feasible that in the same way that sustained internalization of histamine H2 receptor led to upregulation on histamine H2 receptor levels, sustained cointernalization of histamine H1 receptor by ranitidine treatment may also lead to upregulation of histamine H1 receptor, which may explain the observed anaphylactoid reaction after cessation of ranitidine treatment. In conclusion, our findings support the notion that the crosstalk between histamine H1 and H2 receptor signaling is not restrictive to agonist ligands and, as a result, may have profound consequences regarding treatment with histamine H1 and H2 receptor antagonists/inverse agonists. Receptor agonists crossregulate receptor inverse agonists response and receptor inverse agonists crossregulate histamine response. Considering the large number of cell types in different tissues that express histamine H1 and H2 receptors, the clinically widespread use of antagonists/inverse agonists acting through both receptors in the treatment of several human diseases, and the advantage of drug repositioning, the accurate characterization of ligands´ mechanisms of action should allow us to reinterpret side effects of drugs and/or to ascribe new uses.
    Acknowledgements This work was supported by grants from the Agencia Nacional de Promoción Científica y Tecnológica (PICT2013-0495, PICT2016-1821), and from CONICET (PIP 2013-562), as well as from Fundación René Barón and Fundación Williams.
    Introduction As an aminergic multifunctional neurotransmitter, histamine [2-(4-1H-imidazolyl)ethylamine] plays versatile roles in a wide variety of physiological processes and is therefore also implicated in several pathological conditions (Celanire, Wijtmans, Talaga, Leurs, & de Esch, 2005; Gemkow et al., 2009; Nikolic, Filipic, Agbaba, & Stark, 2014). Histamine is produced in a large number of tissues by cells such as mast cells, parietal cells of the gastric mucosa, and neurons of central/peripheral nervous system via decarboxylation of L-histidine by histidine decarboxylase (HDC). Histamine inactivation occurs via two major metabolic pathways, N-methylation and oxidation. In mammalian brain histamine N-methyltransferase (HNMT) catalyzes the methylation of histamine to the H3R inactive Nτ-methylhistamine, whereas monoamine oxidase and aldehyde oxidase are responsible for the formation of (Nτ-methyl)imidazole acetic acid by the metabolic oxidation of histamine and to some extent of Nτ-methylhistamine (Berlin, Boyce, & Ruiz Mde, 2011; Lemke, Williams, & Foye, 2013). Histamine exerts its actions through the activation of four distinct receptor subtypes (H1 to H4), that belong to the class A family of G protein-coupled receptors (GPCRs) (Leurs, Bakker, Timmerman, & de Esch, 2005; Nikolic et al., 2014). Among the histamine receptors, the H3 receptor (H3R) is a pre-synaptically located autoreceptor that inhibits the synthesis and release of histamine. In addition, H3Rs function as pre-synaptic heteroreceptors with inhibitory activity on the release of several neurotransmitters, namely acetylcholine, γ-aminobutyric acid (GABA), dopamine, serotonin, noradrenaline and glutamate (Esbenshade et al., 2008). The H3R was discovered in 1983 by Arrang et al. by analyzing the inhibition of histamine release in depolarized slices of rat cerebral cortex (Arrang, Garbarg, & Schwartz, 1983). In 1987, the presence of the receptor was confirmed by the development of R-α-methylhistamine and thioperamide as selective H3 receptor agonist and antagonist, respectively (Arrang et al., 1987). Later, in 1999 Lovenberg and co-workers cloned the gene of the human H3R, which code for a 445 amino acid protein (Lovenberg et al., 1999). The H3R is predominantly concentrated in the central nervous system (CNS); however, it is also expressed peripherally in the gastrointestinal tract, the airways, and the cardiovascular system (Celanire et al., 2005; Tiligada, Zampeli, Sander, & Stark, 2009).