The histamine H receptor H R
The histamine H3 receptor (H3R; 326–445 amino-acids) is located on histaminergic neuron somata, dendrites and axon varicosities, as well as on the axon varicosities and somata of other neurons, providing negative feedback to inhibit histamine synthesis and the release of histamine or other transmitters, including glutamate, acetylcholine, and GABA. However, vast majority of H3Rs are postsynaptically present in the basal ganglia and especially within the dorsal and ventral striatum. H3R is coupled to Gi/o to inhibit adenylyl cyclase and the high voltage activated Ca channels that are responsible for regulation of histamine synthesis and the neurotransmitter release. Other signaling pathways have been reported to be involved in H3R activation, such as the inhibition of the Na+/H+ exchanger (Karmazyn, 1999), the enhancement of G protein-gated inwardly rectifying K+ channels (Sahlholm, Nilsson, Marcellino, Fuxe, & Arhem, 2012), phospholipase C activation (Coge et al., 2001), the mitogen-activated protein kinase (MAPK) pathway (Drutel et al., 2001), and the phosphatidylinositol 3-kinase (PI3K) pathway (Bongers et al., 2007). The histamine H4 receptor (H4R) was recently discovered, and is predominantly expressed in immune cells, including mast cells, eosinphils and dendritic cells. In the brain, H4R is present in microglia besides mast cells, however its function in these I-BET151 mg remains mysterious. Thus far, there has been no convincing evidence confirming the expression of H4R in neurons, which is due to flawed methods used for detection (Schneider & Seifert, 2016). Further studies from independent research groups will be necessary with more robust techniques including the use of monoclonal anti-H4R antibodies, qPCR experiments, and concentration dependent stimulation of H4R by agonists. H4R shares ~40% homology with H3R, and belongs to the class of Gi/Go-coupled GPCRs that function to reduce cAMP accumulation. In addition, activation of the H4 receptor has also been shown to increase Ca mobilization and activate kinases (ERK, PI3K, and MAPK) and transcription factor activating protein-1 (Dong et al., 2014, Jemima et al., 2014). Despite their importance, H1R or H2R agonists have not been directly applied in clinic due to their broad and largely undesirable peripheral action. The first generation of H1R antagonists, including diphenhydramine, promethazine, tripelennamine, and chlorphenamine, have been shown to penetrate the brain blood barrier (BBB), and often show strong sedative effects. Also, anticholinergic activities were often found in first generation histamine H1R antagonists. The second generation of H1R antagonists (cetirizine, terfanadine, astemizole, and loratadine, et al.) has displayed long-term action, but showed weak sedative and anticholinergic effects with a relatively poor capacity for BBB penetration (Yanai et al., 1995a, Yanai et al., 1995b). Among these second generation antagonists, terfenadine and astemizole have both been withdrawn from the market due to their cardiotoxicity. Third generation H1R antagonists are active enantiomers (levocetirizine) and metabolites (desloratadine and fexofenadine) of the second generation H1R antagonists. Fexofenadine has been associated with a decreased risk of cardiac arrhythmia compared to terfenadine. In contrast, there is almost no advantage of levocetirizine or desloratadine, compared to cetirizine or loratadine, respectively, so the term “third generation” should be used with caution (Camelo-Nunes, 2006, Kalpaklioglu and Baccioglu, 2012). The sedative effects of H1R antagonists were initially recognized as side effects for the treatment of allergic rhinitis, but such action is responsible for the use of the induction of sleep. Due to blockage of H1R in the emetic center, H1R antagonists are also often used for the treatment of motion sickness. However, a recent study emphasized the need for caution in the application of such drugs in older hospitalized patients because there have been putative links to the onset of delirium (Rothberg et al., 2013), and H1R antagonists may also affect cognitive functioning to different extents and increase the susceptibility of patients to seizures (Hu et al., 2012, Simons et al., 1996). Moreover, H1R is found to be occupied by other drugs, such as antidepressants mirtazapine and antipsychotics olanzapine and quetiapine from positron emission tomography study in humans (Sato et al., 2013, Sato et al., 2015). Therefore, further evidence is needed to elucidate the role of H1R in CNS disorders, and this knowledge will be used to guide the development of a new generation of H1R antagonists.