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Review

Histamine N-Methyltransferase in the Brain

1
Department of Pharmacology, Tohoku University Graduate School of Medicine, 2-1, Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
2
Division of Pharmacology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, 1-15-1, Fukumuro, Miyagino-ku, Sendai 983-8536, Japan
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(3), 737; https://doi.org/10.3390/ijms20030737
Received: 24 January 2019 / Revised: 8 February 2019 / Accepted: 8 February 2019 / Published: 10 February 2019
(This article belongs to the Special Issue Histamine-Related Molecules as Therapeutic Targets)

Abstract

Brain histamine is a neurotransmitter and regulates diverse physiological functions. Previous studies have shown the involvement of histamine depletion in several neurological disorders, indicating the importance of drug development targeting the brain histamine system. Histamine N-methyltransferase (HNMT) is a histamine-metabolising enzyme expressed in the brain. Although pharmacological studies using HNMT inhibitors have been conducted to reveal the direct involvement of HNMT in brain functions, HNMT inhibitors with high specificity and sufficient blood–brain barrier permeability have not been available until now. Recently, we have phenotyped Hnmt-deficient mice to elucidate the importance of HNMT in the central nervous system. Hnmt disruption resulted in a robust increase in brain histamine concentration, demonstrating the essential role of HNMT in the brain histamine system. Clinical studies have suggested that single nucleotide polymorphisms of the human HNMT gene are associated with several brain disorders such as Parkinson’s disease and attention deficit hyperactivity disorder. Postmortem studies also have indicated that HNMT expression is altered in human brain diseases. These findings emphasise that an increase in brain histamine levels by novel HNMT inhibitors could contribute to the improvement of brain disorders.
Keywords: diamine oxidase; histamine; histamine H3 receptor; histamine N-methyltransferase diamine oxidase; histamine; histamine H3 receptor; histamine N-methyltransferase

1. Introduction

Histamine (2-[4-imidazolyl]ethylamine) was discovered by Sir Henry Hallet Dale and Sir Patrick Playfair Laidlaw in 1910 [1]. Histamine mediates a wide variety of events such as allergic reactions, gastric acid secretion, and smooth muscle contraction through interaction with four histamine receptor subtypes (H1R–H4R). Pharmacological research targeting histamine action in peripheral organs has led to the development of drugs such as H1R antagonists for allergic diseases and H2R antagonists for gastric ulcers. This amine also acts as a neurotransmitter in the brain [2]. Histaminergic neurons are located in the tuberomammillary nucleus of the hypothalamus and project their axons into various brain regions including the cerebral cortex, hypothalamus, basal ganglia, and amygdala [3]. The number of histamine-producing neurons in the human brain is estimated to be approximately 64,000. Brain histamine regulates diverse physiological functions such as sleep–wake cycles, stress response, appetite, and memory. Extensive investigations have shown the pathophysiological involvement of the histaminergic nervous system in various neuropsychiatric disorders. A loss-of-function mutation of the histidine decarboxylase (HDC) gene (EC 4.1.1.22), the essential enzyme for histamine production, is associated with Tourette’s syndrome [4]. Pathological changes in histamine neurons are involved in cognitive impairment [5,6,7]. The reduction in histamine concentration in the cerebrospinal fluid was observed in narcolepsy patients [8,9,10]. H1R binding potential was found to be decreased in patients with depression and schizophrenia (SCZ) via positron emission tomography [11,12]. This evidence suggests that the dysfunction of the histaminergic nervous system could play a causative role in various neurological disorders and that the increase in brain histamine might have therapeutic potential.
Over the past few decades, H3R receptors in the brain have attracted attention as therapeutic targets to modulate the histamine system. This receptor identified by Arrang et al. in 1983 is a Gi/o protein-coupled receptor and negatively regulates histamine release as a presynaptic autoreceptor at nerve end terminals [2,13]. H3R inverse agonists, which could induce histamine release, were developed by many pharmaceutical companies and were examined for their therapeutic effects on animal models for neurological disorders and also on patients suffering from brain diseases [14,15]. Although the beneficial effect of most H3R inverse agonists is inconclusive, pitolisant, an H3R antagonist developed by Schwartz et al. [16], was approved for the treatment of narcolepsy by the European Medical Agency in 2016 [17], emphasising the involvement of histamine concentration in brain functions.
Neurotransmitter clearance is very important for maintaining normal neurotransmitter concentration. The neurotransmitters released into extracellular spaces are cleared by transporters and /or enzymes in the adjacent neurons or astrocytes to avoid excessive neuronal activation. Dysfunctional neurotransmitter clearance plays a causative role in various neurological disorders, including SCZ and depression. Indeed, various drugs, such as tricyclic antidepressants, serotonin norepinephrine re-uptake inhibitors, and monoamine oxidase inhibitors, block neurotransmitter clearance and exert their therapeutic actions in patients suffering from brain diseases. This evidence supports that histamine clearance machinery could be a therapeutic target for developing novel drugs that improve brain functions. However, the mechanism of brain histamine clearance had not been clarified.
Previous studies using rodents showed that astrocytes play an important role in histamine clearance [18]. We recently investigated the molecular mechanism of histamine clearance using primary human astrocytes [19]. Our in vitro experiments showed that human astrocytes transport histamine dominantly through plasma membrane monoamine transporter (PMAT) and also through organic cation transporter 3 (OCT3). Next, the histamine transported into the cytosol is metabolised by histamine N-methyltransferase (HNMT) (EC 2.1.1.8) (Figure 1). PMAT and OCT3, which are polyspecific transporters, transport various monoamines, including serotonin, dopamine, norepinephrine, and histamine [20]. PMAT, which was identified in 2004, is widely distributed in the brain [21,22]. Several reports suggested that PMAT plays a role in serotonin clearance [23,24], and that mutations in the human PMAT genes coupled with low transport activity are related to autism spectrum disorders [25], indicating the involvement of PMAT in brain monoamine concentration. However, Pmat deficiency in mice does not greatly affect brain histamine concentration under non-stressful conditions (our unpublished observation) nor induces behavioural abnormalities [26]. OCT3 is expressed in different brain regions including the cerebral cortex, hippocampus, and cerebellum [27]. The contribution of OCT3 to serotonin and dopamine concentrations has already been reported [28,29]. Zhu et al. examined the importance of OCT3 in brain histamine concentration [30]. They showed that OCT3 is not involved in brain histamine concentration in normal conditions, whereas histamine content in the brain cortex is elevated in Oct3-deficient mice after cerebral ischemia. These results might indicate the minor contribution of these transporters to brain histamine concentration, although further studies are essential to examine the importance of PMAT and OCT3 in histamine clearance. In contrast, our recent study using Hnmt knockout mice clearly showed that Hnmt plays a predominant role in brain histamine concentration and the regulation of the histaminergic nervous system [31]. In this article, we focus on HNMT function in the central nervous system (CNS).

2. Histamine-Metabolising Enzymes

There are two different enzymes for the inactivation of histamine: diamine oxidase (DAO) (EC 1.4.3.22) and HNMT. DAO, also known as histaminase, is the product of the AOC1 gene. DAO acts as a homodimeric protein to oxidatively deaminate various amines including histamine, putrescine, and spermidine [35,36]. DAO is highly expressed in the digestive tract. The Km (Michaelis constant) value of human intestinal DAO to histamine was calculated as 19 µM [37]. DAO plays a role in detoxification of dietary histamine to reduce histamine uptake through enterocytes. Thus, impaired DAO activity results in the increase of histamine absorption and the elevation of blood histamine concentration. Although DAO is also highly expressed in the kidneys and placenta, DAO expression in the CNS is low or absent [38], indicating that DAO metabolises histamine in the peripheral organs but not the CNS.
HNMT is an enzyme catalysing the transfer of a methyl group from S-adenosyl-l-methionine (SAM) to histamine, yielding Nτ-methylhistamine and S-adenosyl-l-homocysteine (Figure 2). The human HNMT gene was cloned by Girard et al. in 1994 and encodes a 33 kDa protein consisting of 292 amino acids [39] (Table 1). Although HNMT is widely observed in vertebrates including humans, rodents, birds, lizards, and amphibians, the expression of HNMT has not been confirmed in invertebrates and plants. In mammals, HNMT is widely expressed in various organs including liver, kidney, and brain [40]; and methylated histamine metabolites are abundantly excreted in urine [41], suggesting the important role of HNMT in histamine metabolism. Brain HNMT activity in the CNS was first detected in the soluble supernatant fraction from guinea pig brain in 1959 [42]. Schayer and Reilly confirmed the existence of methylated histamine inactivated by HNMT in guinea pig brain [43]. Human HNMT activity has also been detected in the frontal, temporal, parietal, occipital, and cerebellar cortices [44]. The Human Protein Atlas project showed a high expression of HNMT in the cerebellum and medium expression in the cerebral cortex, hippocampus, and caudate [45]. The project also found that both neurons and glial cells express HNMT. An in situ hybridisation study in Allen Mouse Brain Atlas showed the highest mRNA expression of HNMT in the cortical subplate [46]. Northern blot analysis using mouse and rat brains revealed ubiquitous expression of Hnmt except in rat cerebellum and mouse striatum [47]. Immunohistochemical analysis using bovine brain revealed that several neurons including the oculomotor nucleus, red nucleus, facial nucleus, and dorsal vagal nucleus strongly express Hnmt [33]. However, the detailed distribution of brain HNMT in mice, rats, and humans is still unknown. Further immunohistochemical analysis using specific antibodies is essential to understanding detailed HNMT distribution in the CNS.

3. HNMT and Human Brain Diseases

The effects of genetic polymorphism of human HNMT on enzymatic activity was first reported by Preuss et al. in 1998 [40]. They showed that a C-to-T transition at nucleotide 314 (C314T) in exon 4 replaces threonine with isoleucine at codon 105 (Thr105Ile), leading to decreased enzymatic activity. Although amino acid residue 105 is distal from the substrate binding sites, the C314T polymorphism has a great impact on active site structure and dynamics, resulting in the increased Km value of human HNMT for histamine and SAM by 1.3- and 1.8-fold, respectively [52,53]. Several groups examined the association of C314T polymorphism with Parkinson’s disease (PD) [54,55,56,57], and the meta-analysis of these four studies suggested a protective role of this polymorphism against the development of PD [58] (Table 2). Other genetic association studies suggested the involvement of the C314T substitution in SCZ [57], attention deficit hyperactivity disorder (ADHD) [59] and migraine [60] but not in Alzheimer’s disease (AD) [61], amyotrophic lateral sclerosis [62], multiple sclerosis [63], or restless legs syndrome [64]. The effect of the C314T polymorphism on alcoholism was inconclusive [65,66]. An A-to-G polymorphism at nucleotide 939 in the 3′ untranslated region of the human HNMT gene increases HNMT mRNA stability and increases HNMT protein, and enhances enzymatic activity [67]. An A939G polymorphism is related to several brain disorders such as myasthenia gravis and ADHD [59,68]. Recently, Heidari et al. reported that two novel mutations in the human HNMT gene (G179A and T632C) impairs its enzymatic activity, leading to intellectual disability [69,70].
Several postmortem studies examined the alteration of HNMT expression in neurological disorders. HNMT expression was increased at the inferior frontal gyrus in Huntington’s disease [71], at the substantia nigra and putamen in PD [72], and at the frontal cortex in Pick’s disease [73]. HNMT mRNA expression was also elevated in the prefrontal cortex of female AD patients [74]. On the other hand, HNMT expression was reduced at the anterior cingulated cortex in depression [75] and the frontal cortex in Down syndrome [73]. Although these results indicate the possible involvement of HNMT functions in neuropsychiatric disorders, it is still unknown whether alterations in HNMT activity exert the causative role in disease progression, play a compensatory function for impaired brain functions, or is a secondary outcome accompanied by primary pathological change. Therefore, these associations should be validated in larger studies and possibly by prospective clinical studies in the near future.

4. Pharmacological Analysis Using HNMT Inhibitors

Duch and colleagues discovered that metoprine, a derivative of 2,4-diaminopyrimidine, inhibited HNMT activity with a Ki value of 100 nM [76,77]. Because metoprine can cross the blood–brain barrier (BBB) due to its hydrophobicity (logP = 2.82) and increase brain histamine concentration [78], many researchers have used this inhibitor to investigate the role of HNMT in the CNS. Pharmacological studies using metoprine indicated that the activation of the histaminergic system in the CNS affects a wide variety of brain functions such as antinociception [79], suppression of energy intake [80], hyperglycaemic action [81], improvement of cognitive function [82], antiepileptic effect [83,84,85], and attenuation of methamphetamine-induced behavioural abnormalities [86]. However, metoprine can also inhibit mammalian dihydrofolate reductase (EC 1.5.1.3) and decrease cellular folate metabolism, resulting in the attenuation of cell growth [87,88]; therefore, it cannot be ruled out that the low specificity of metoprine affected the results. Another HNMT inhibitor, SKF91488, developed by Beaven et al. can specifically inhibit the enzymatic activity devoid of histamine receptor agonist activity [89]. Unfortunately, due to the poor BBB permeability of SKF91488, the brain research using SKF91488 has been limited [90,91,92]. Therefore, novel HNMT inhibitors with high specificity and sufficient BBB permeability are expected to accelerate to pharmacological research on brain HNMT. Properties of commercially available HNMT inhibitors are summarised in Table 3 and Figure 3.

5. Phenotyping of Hnmt-deficient Mice

Recently, we phenotyped Hnmt-knockout (KO) mice for a better understanding of the role played by HNMT in brain function [31]. First, we showed that histamine content from the cortices, diencephalons, brainstems, and cerebella of KO mice was at least 5-fold higher than that of wild-type (WT) mice. Histamine concentration was consistently higher in whole brain homogenates from neonatal, adolescent, and adult KO mice compared with those of WT mice. Higher extraneuronal histamine concentration in KO mice was also confirmed by in vivo microdialysis assay. However, other monoamines and their metabolites were not changed in KO mouse brains. Histamine concentration in several organs such as the skin and stomach was not elevated. These results demonstrated that Hnmt affected extracellular and intracellular histamine concentration of mouse brains throughout development and adult life. Next, we performed comprehensive behavioural testing to investigate the impact of elevated histamine on mouse behaviours. Although KO mice did not show anxiety-like behaviours, depression-like behaviours, impaired memory, or impaired motor function, highly aggressive behaviours and decreased locomotor activity in home cages were observed in KO mice. High aggression in KO mice was attenuated by pre-treatment of H2R antagonist zolantidine but not by H1R antagonist pyrilamine, indicating that elevated histamine by Hnmt deficiency activated H2R, thereby driving aggressive behaviours in mice. The decreased locomotor activity in home cages suggested that the sleep–wake cycle was disrupted in KO mice, resulting in extended immobility during periods that should have been active. Sleep analysis with electroencephalography and electromyography showed prolonged wakefulness during the inactive period and compensatory sleep during the active period. The average wake bout duration was increased in KO mice during zeitgeber time (ZT) 0–6 compared to WT mice, although the total number of wake and sleep bouts was not changed by Hnmt deficiency. Pyrilamine injection at ZT0 normalised both the prolonged wakefulness during ZT0–6 and the decreased wakefulness during ZT12–18 in KO mice, indicating that excessive H1R activation disrupted the sleep–wake cycle in KO mice. These results demonstrated that HNMT played an essential role in regulating brain histamine concentration and accordingly controls aggression and sleep–wake cycles. In this study, we deleted whole body Hnmt to understand the histaminergic nervous system using conventional knockout technology. We could not rule out the possibility that alteration of peripheral organ function might have affected brain functions. Thus, focal disruption of Hnmt in adult mice using an adeno-associated virus vector should be utilised to determine brain regions responsible for the aggression and sleep–wake abnormalities. It is also of interest to examine the behavioural changes of KO mice under stressful conditions such as sleep deprivation and social defeat stress so that better understanding of the role of HNMT in psychiatric diseases can be gained. Moreover, the role of Hnmt in rodent models of neurodegenerative disorders including PD and AD should be examined because several clinical studies showed alteration of the histaminergic nervous system in these disorders. Further studies are essential to confirm and extend our findings in rodent models and, eventually, in humans.

6. Future Perspectives

As mentioned above, dysfunction of the histaminergic nervous system is associated with various neuropsychiatric disorders including narcolepsy, AD, Tourette’s syndrome, eating disorders, and depression. Animal experiments using H3R inverse agonists or HNMT inhibitors suggest the therapeutic effect of histamine elevation on brain function [96]. Dietary intake of histidine, as a precursor of histamine, also improved memory functions via the histamine system in rodents (unpublished observation) and ameliorated feelings of fatigue in humans [97]. The marked effect of HNMT on brain histamine concentration indicates the strong therapeutic potential of HNMT inhibitors against brain diseases. Hnmt disruption enhanced brain histamine levels by >6-fold [31], whereas the impact of H3R antagonists on brain histamine was quite weak (<2-fold) [98]. Injection of a H3R inverse agonist ciproxifan transiently increased histamine release in mouse brains; however, the reduced histamine release was observed 24 h after the injection, possibly due to the development of receptor hypersensitivity or endogenous histamine deletion [99]. Theoretically, HNMT inhibitors do not induce histamine depletion. These results indicate that HNMT inhibitors might have some advantages over H3R inverse agonists. Nevertheless, HNMT inhibitors might increase peripheral tissue histamine levels and exacerbate histamine-related diseases such as allergic rhinitis, urticaria, and gastric ulcers, as HNMT is also expressed in peripheral tissues. Several reports have shown that C314T polymorphisms of the HNMT gene is not associated with allergic asthma and rhinitis [100,101,102], although a case-control study in Poland indicated the association of this polymorphism with asthma [103]. We confirmed that Hnmt disruption did not affect histamine concentration of the skin and stomach [31]. Thus, adverse effects induced by HNMT inhibition in the peripheral tissues might be negligible, although we could not rule out the possibility that HNMT inhibitors might aggravate allergic rhinitis, skin diseases, and peptic ulcers. Taken together, it is intriguing to find novel HNMT inhibitors with high specificity and sufficient BBB permeability. We hope that prominent HNMT inhibitors will help many patients who suffer from brain diseases.

Author Contributions

Wrote the manuscript: T.Y., T.N. and K.Y.

Funding

This work was supported by a Grant-in-Aid for Scientific Research (A) (26253016) from the Japan Society for the Promotion of Science (JSPS) and by a Grant-in-Aid for Scientific Research (C) (18K06886), also from JSPS. We also acknowledge the support of the Nishinomiya Basic Research Fund, Japan and Takeda Science Foundation, Japan.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Dale, H.H.; Laidlaw, P.P. The physiological action of beta-iminazolylethylamine. J. Physiol. 1910, 41, 318–344. [Google Scholar] [CrossRef] [PubMed]
  2. Haas, H.L.; Sergeeva, O.A.; Selbach, O. Histamine in the nervous system. Physiol. Rev. 2008, 88, 1183–1241. [Google Scholar] [CrossRef] [PubMed]
  3. Watanabe, T.; Taguchi, Y.; Shiosaka, S.; Tanaka, J.; Kubota, H.; Terano, Y.; Tohyama, M.; Wada, H. Distribution of the histaminergic neuron system in the central nervous system of rats; a fluorescent immunohistochemical analysis with histidine decarboxylase as a marker. Brain Res. 1984, 295, 13–25. [Google Scholar] [CrossRef]
  4. Baldan, L.C.; Williams, K.A.; Gallezot, J.D.; Pogorelov, V.; Rapanelli, M.; Crowley, M.; Anderson, G.M.; Loring, E.; Gorczyca, R.; Billingslea, E.; et al. Histidine decarboxylase deficiency causes tourette syndrome: Parallel findings in humans and mice. Neuron 2014, 81, 77–90. [Google Scholar] [CrossRef] [PubMed]
  5. Zlomuzica, A.; Dere, D.; Binder, S.; De Souza Silva, M.A.; Huston, J.P.; Dere, E. Neuronal histamine and cognitive symptoms in Alzheimer’s disease. Neuropharmacology 2016, 106, 135–145. [Google Scholar] [CrossRef] [PubMed]
  6. Mazurkiewicz-Kwilecki, I.M.; Nsonwah, S. Changes in the regional brain histamine and histidine levels in postmortem brains of Alzheimer patients. Can. J. Physiol. Pharmacol. 1989, 67, 75–78. [Google Scholar] [CrossRef] [PubMed]
  7. Panula, P.; Rinne, J.; Kuokkanen, K.; Eriksson, K.S.; Sallmen, T.; Kalimo, H.; Relja, M. Neuronal histamine deficit in Alzheimer’s disease. Neuroscience 1998, 82, 993–997. [Google Scholar] [CrossRef]
  8. Nishino, S.; Sakurai, E.; Nevsimalova, S.; Yoshida, Y.; Watanabe, T.; Yanai, K.; Mignot, E. Decreased CSF histamine in narcolepsy with and without low CSF hypocretin-1 in comparison to healthy controls. Sleep 2009, 32, 175–180. [Google Scholar] [CrossRef]
  9. Kanbayashi, T.; Kodama, T.; Kondo, H.; Satoh, S.; Inoue, Y.; Chiba, S.; Shimizu, T.; Nishino, S. CSF histamine contents in narcolepsy, idiopathic hypersomnia and obstructive sleep apnea syndrome. Sleep 2009, 32, 181–187. [Google Scholar] [CrossRef]
  10. Bassetti, C.L.; Baumann, C.R.; Dauvilliers, Y.; Croyal, M.; Robert, P.; Schwartz, J.C. Cerebrospinal fluid histamine levels are decreased in patients with narcolepsy and excessive daytime sleepiness of other origin. J. Sleep Res. 2010, 19, 620–623. [Google Scholar] [CrossRef][Green Version]
  11. Iwabuchi, K.; Ito, C.; Tashiro, M.; Kato, M.; Kano, M.; Itoh, M.; Iwata, R.; Matsuoka, H.; Sato, M.; Yanai, K. Histamine H1 receptors in schizophrenic patients measured by positron emission tomography. Eur. Neuropsychopharmacol. 2005, 15, 185–191. [Google Scholar] [CrossRef] [PubMed]
  12. Kano, M.; Fukudo, S.; Tashiro, A.; Utsumi, A.; Tamura, D.; Itoh, M.; Iwata, R.; Tashiro, M.; Mochizuki, H.; Funaki, Y.; et al. Decreased histamine H1 receptor binding in the brain of depressed patients. Eur. J. Neurosci. 2004, 20, 803–810. [Google Scholar] [CrossRef] [PubMed]
  13. Arrang, J.M.; Garbarg, M.; Schwartz, J.C. Auto-inhibition of brain histamine release mediated by a novel class (H3) of histamine receptor. Nature 1983, 302, 832–837. [Google Scholar] [CrossRef] [PubMed]
  14. Passani, M.B.; Blandina, P. Histamine receptors in the CNS as targets for therapeutic intervention. Trends Pharmacol. Sci 2011, 32, 242–249. [Google Scholar] [CrossRef] [PubMed]
  15. Leurs, R.; Bakker, R.A.; Timmerman, H.; de Esch, I.J. The histamine H3 receptor: From gene cloning to H3 receptor drugs. Nat. Rev. Drug Discov. 2005, 4, 107–120. [Google Scholar] [CrossRef] [PubMed]
  16. Schwartz, J.C. The histamine H3 receptor: From discovery to clinical trials with pitolisant. Br. J. Pharmacol. 2011, 163, 713–721. [Google Scholar] [CrossRef]
  17. Syed, Y.Y. Pitolisant: First Global Approval. Drugs 2016, 76, 1313–1318. [Google Scholar] [CrossRef]
  18. Huszti, Z. Histamine uptake into non-neuronal brain cells. Inflamm. Res. 2003, 52, S3–S6. [Google Scholar] [CrossRef]
  19. Yoshikawa, T.; Naganuma, F.; Iida, T.; Nakamura, T.; Harada, R.; Mohsen, A.S.; Kasajima, A.; Sasano, H.; Yanai, K. Molecular mechanism of histamine clearance by primary human astrocytes. Glia 2013, 61, 905–916. [Google Scholar] [CrossRef]
  20. Yoshikawa, T.; Yanai, K. Histamine Clearance Through Polyspecific Transporters in the Brain. Handb. Exp. Pharmacol. 2017, 241, 173–187. [Google Scholar]
  21. Engel, K.; Zhou, M.; Wang, J. Identification and characterization of a novel monoamine transporter in the human brain. J. Biol. Chem. 2004, 279, 50042–50049. [Google Scholar] [CrossRef] [PubMed]
  22. Dahlin, A.; Xia, L.; Kong, W.; Hevner, R.; Wang, J. Expression and immunolocalization of the plasma membrane monoamine transporter in the brain. Neuroscience 2007, 146, 1193–1211. [Google Scholar] [CrossRef] [PubMed][Green Version]
  23. Daws, L.C.; Koek, W.; Mitchell, N.C. Revisiting serotonin reuptake inhibitors and the therapeutic potential of “uptake-2” in psychiatric disorders. ACS Chem. Neurosci. 2013, 4, 16–21. [Google Scholar] [CrossRef] [PubMed]
  24. Matthaeus, F.; Schloss, P.; Lau, T. Differential Uptake Mechanisms of Fluorescent Substrates into Stem-Cell-Derived Serotonergic Neurons. ACS Chem. Neurosci. 2015, 6, 1906–1912. [Google Scholar] [CrossRef]
  25. Adamsen, D.; Ramaekers, V.; Ho, H.T.; Britschgi, C.; Rufenacht, V.; Meili, D.; Bobrowski, E.; Philippe, P.; Nava, C.; Van Maldergem, L.; et al. Autism spectrum disorder associated with low serotonin in CSF and mutations in the SLC29A4 plasma membrane monoamine transporter (PMAT) gene. Mol. Autism. 2014, 5, 43. [Google Scholar] [CrossRef] [PubMed]
  26. Duan, H.; Wang, J. Impaired monoamine and organic cation uptake in choroid plexus in mice with targeted disruption of the plasma membrane monoamine transporter (Slc29a4) gene. J. Biol. Chem. 2013, 288, 3535–3544. [Google Scholar] [CrossRef] [PubMed]
  27. Wu, X.; Kekuda, R.; Huang, W.; Fei, Y.J.; Leibach, F.H.; Chen, J.; Conway, S.J.; Ganapathy, V. Identity of the organic cation transporter OCT3 as the extraneuronal monoamine transporter (uptake2) and evidence for the expression of the transporter in the brain. J. Biol. Chem. 1998, 273, 32776–32786. [Google Scholar] [CrossRef]
  28. Baganz, N.L.; Horton, R.E.; Calderon, A.S.; Owens, W.A.; Munn, J.L.; Watts, L.T.; Koldzic-Zivanovic, N.; Jeske, N.A.; Koek, W.; Toney, G.M.; et al. Organic cation transporter 3: Keeping the brake on extracellular serotonin in serotonin-transporter-deficient mice. Proc. Natl. Acad. Sci. USA 2008, 105, 18976–18981. [Google Scholar] [CrossRef][Green Version]
  29. Cui, M.; Aras, R.; Christian, W.V.; Rappold, P.M.; Hatwar, M.; Panza, J.; Jackson-Lewis, V.; Javitch, J.A.; Ballatori, N.; Przedborski, S.; et al. The organic cation transporter-3 is a pivotal modulator of neurodegeneration in the nigrostriatal dopaminergic pathway. Proc. Natl. Acad. Sci. USA 2009, 106, 8043–8048. [Google Scholar] [CrossRef][Green Version]
  30. Zhu, P.; Hata, R.; Ogasawara, M.; Cao, F.; Kameda, K.; Yamauchi, K.; Schinkel, A.H.; Maeyama, K.; Sakanaka, M. Targeted disruption of organic cation transporter 3 (Oct3) ameliorates ischemic brain damage through modulating histamine and regulatory T cells. J. Cereb. Blood Flow Metab. 2012, 32, 1897–1908. [Google Scholar] [CrossRef]
  31. Naganuma, F.; Nakamura, T.; Yoshikawa, T.; Iida, T.; Miura, Y.; Karpati, A.; Matsuzawa, T.; Yanai, A.; Mogi, A.; Mochizuki, T.; et al. Histamine N-methyltransferase regulates aggression and the sleep-wake cycle. Sci. Rep. 2017, 7, 15899. [Google Scholar] [CrossRef] [PubMed]
  32. Naganuma, F.; Yoshikawa, T.; Nakamura, T.; Iida, T.; Harada, R.; Mohsen, A.S.; Miura, Y.; Yanai, K. Predominant role of plasma membrane monoamine transporters in monoamine transport in 1321N1, a human astrocytoma-derived cell line. J. Neurochem. 2014, 129, 591–601. [Google Scholar] [CrossRef] [PubMed][Green Version]
  33. Nishibori, M.; Tahara, A.; Sawada, K.; Sakiyama, J.; Nakaya, N.; Saeki, K. Neuronal and vascular localization of histamine N-methyltransferase in the bovine central nervous system. Eur. J. Neurosci. 2000, 12, 415–424. [Google Scholar] [CrossRef] [PubMed]
  34. Sakurai, E.; Sakurai, E.; Oreland, L.; Nishiyama, S.; Kato, M.; Watanabe, T.; Yanai, K. Evidence for the presence of histamine uptake into the synaptosomes of rat brain. Pharmacology 2006, 78, 72–80. [Google Scholar] [CrossRef] [PubMed]
  35. Maintz, L.; Novak, N. Histamine and histamine intolerance. Am. J. Clin. Nutr. 2007, 85, 1185–1196. [Google Scholar] [CrossRef] [PubMed][Green Version]
  36. McGrath, A.P.; Hilmer, K.M.; Collyer, C.A.; Shepard, E.M.; Elmore, B.O.; Brown, D.E.; Dooley, D.M.; Guss, J.M. Structure and inhibition of human diamine oxidase. Biochemistry 2009, 48, 9810–9822. [Google Scholar] [CrossRef] [PubMed]
  37. Bieganski, T.; Kusche, J.; Lorenz, W.; Hesterberg, R.; Stahlknecht, C.D.; Feussner, K.D. Distribution and properties of human intestinal diamine oxidase and its relevance for the histamine catabolism. Biochim. Biophys. Acta 1983, 756, 196–203. [Google Scholar] [CrossRef]
  38. Elmore, B.O.; Bollinger, J.A.; Dooley, D.M. Human kidney diamine oxidase: Heterologous expression, purification, and characterization. J. Biol. Inorg. Chem. 2002, 7, 565–579. [Google Scholar] [CrossRef]
  39. Girard, B.; Otterness, D.M.; Wood, T.C.; Honchel, R.; Wieben, E.D.; Weinshilboum, R.M. Human histamine N-methyltransferase pharmacogenetics: Cloning and expression of kidney cDNA. Mol. Pharmacol. 1994, 45, 461–468. [Google Scholar]
  40. Preuss, C.V.; Wood, T.C.; Szumlanski, C.L.; Raftogianis, R.B.; Otterness, D.M.; Girard, B.; Scott, M.C.; Weinshilboum, R.M. Human histamine N-methyltransferase pharmacogenetics: Common genetic polymorphisms that alter activity. Mol. Pharmacol. 1998, 53, 708–717. [Google Scholar] [CrossRef] [PubMed]
  41. Cooper, J.A.; Schayer, R.W. Metabolism of C14 histamine in man. J. Appl. Physiol. 1956, 9, 481–483. [Google Scholar] [PubMed]
  42. Brown, D.D.; Tomchick, R.; Axelrod, J. The distribution and properties of a histamine-methylating enzyme. J. Biol. Chem. 1959, 234, 2948–2950. [Google Scholar] [PubMed]
  43. Schayer, R.W.; Reilly, M.A. Metabolism of 14C-histamine in brain. J. Pharmacol. Exp. Ther. 1973, 187, 34–39. [Google Scholar] [PubMed]
  44. Pacifici, G.M.; Donatelli, P.; Giuliani, L. Histamine N-methyl transferase: Inhibition by drugs. Br. J. Clin. Pharmacol. 1992, 34, 322–327. [Google Scholar] [CrossRef] [PubMed]
  45. Uhlen, M.; Fagerberg, L.; Hallstrom, B.M.; Lindskog, C.; Oksvold, P.; Mardinoglu, A.; Sivertsson, A.; Kampf, C.; Sjostedt, E.; Asplund, A.; et al. Proteomics. Tissue-based map of the human proteome. Science 2015, 347, 1260419. [Google Scholar] [CrossRef] [PubMed]
  46. Lein, E.S.; Hawrylycz, M.J.; Ao, N.; Ayres, M.; Bensinger, A.; Bernard, A.; Boe, A.F.; Boguski, M.S.; Brockway, K.S.; Byrnes, E.J.; et al. Genome-wide atlas of gene expression in the adult mouse brain. Nature 2007, 445, 168–176. [Google Scholar] [CrossRef] [PubMed]
  47. Kitanaka, N.; Kitanaka, J.; Oue, T.; Tada, Y.; Tanaka, T.; Takemura, M. Genomic structure of the rat and mouse histamine N-methyltransferase gene. Jpn. J. Pharmacol. 2002, 88, 85–92. [Google Scholar] [CrossRef]
  48. Yamauchi, K.; Sekizawa, K.; Suzuki, H.; Nakazawa, H.; Ohkawara, Y.; Katayose, D.; Ohtsu, H.; Tamura, G.; Shibahara, S.; Takemura, M.; et al. Structure and function of human histamine N-methyltransferase: Critical enzyme in histamine metabolism in airway. Am. J. Physiol. 1994, 267, L342–L349. [Google Scholar] [CrossRef]
  49. Wang, L.; Yan, L.; McGuire, C.; Kozak, C.A.; Wang, M.; Kim, U.J.; Siciliano, M.; Weinshilboum, R.M. Mouse histamine N-methyltransferase: cDNA cloning, expression, gene cloning and chromosomal localization. Inflamm. Res. 2001, 50, 300–308. [Google Scholar] [CrossRef]
  50. Takemura, M.; Tanaka, T.; Taguchi, Y.; Imamura, I.; Mizuguchi, H.; Kuroda, M.; Fukui, H.; Yamatodani, A.; Wada, H. Histamine N-methyltransferase from rat kidney. Cloning, nucleotide sequence, and expression in Escherichia coli cells. J. Biol. Chem. 1992, 267, 15687–15691. [Google Scholar]
  51. Kitanaka, J.; Kitanaka, N.; Tsujimura, T.; Kakihana, M.; Terada, N.; Takemura, M. Guinea pig histamine N-methyltransferase: cDNA cloning and mRNA distribution. Jpn. J. Pharmacol. 2001, 85, 105–108. [Google Scholar] [CrossRef] [PubMed]
  52. Horton, J.R.; Sawada, K.; Nishibori, M.; Zhang, X.; Cheng, X. Two polymorphic forms of human histamine methyltransferase: Structural, thermal, and kinetic comparisons. Structure 2001, 9, 837–849. [Google Scholar] [CrossRef]
  53. Rutherford, K.; Parson, W.W.; Daggett, V. The histamine N-methyltransferase T105I polymorphism affects active site structure and dynamics. Biochemistry 2008, 47, 893–901. [Google Scholar] [CrossRef]
  54. Agundez, J.A.; Luengo, A.; Herraez, O.; Martinez, C.; Alonso-Navarro, H.; Jimenez-Jimenez, F.J.; Garcia-Martin, E. Nonsynonymous polymorphisms of histamine-metabolising enzymes in patients with Parkinson’s disease. Neuromolecular Med. 2008, 10, 10–16. [Google Scholar] [CrossRef] [PubMed]
  55. Keeling, B.H.; Vilarino-Guell, C.; Soto-Ortolaza, A.I.; Ross, O.A.; Uitti, R.J.; Rajput, A.; Wszolek, Z.K.; Farrer, M.J. Histamine N-methyltransferase Thr105Ile is not associated with Parkinson’s disease or essential tremor. Parkinsonism Relat. Disord. 2010, 16, 112–114. [Google Scholar] [CrossRef] [PubMed]
  56. Palada, V.; Terzic, J.; Mazzulli, J.; Bwala, G.; Hagenah, J.; Peterlin, B.; Hung, A.Y.; Klein, C.; Krainc, D. Histamine N-methyltransferase Thr105Ile polymorphism is associated with Parkinson’s disease. Neurobiol. Aging 2012, 33, 836 e1–836 e3. [Google Scholar] [CrossRef]
  57. Yang, X.; Liu, C.; Zhang, J.; Han, H.; Wang, X.; Liu, Z.; Xu, Y. Association of histamine N-methyltransferase Thr105Ile polymorphism with Parkinson’s disease and schizophrenia in Han Chinese: A case-control study. PLoS ONE 2015, 10, e0119692. [Google Scholar] [CrossRef]
  58. Jimenez-Jimenez, F.J.; Alonso-Navarro, H.; Garcia-Martin, E.; Agundez, J.A. Thr105Ile (rs11558538) polymorphism in the histamine N-methyltransferase (HNMT) gene and risk for Parkinson disease: A PRISMA-compliant systematic review and meta-analysis. Medicine (Baltimore) 2016, 95, e4147. [Google Scholar] [CrossRef]
  59. Stevenson, J.; Sonuga-Barke, E.; McCann, D.; Grimshaw, K.; Parker, K.M.; Rose-Zerilli, M.J.; Holloway, J.W.; Warner, J.O. The role of histamine degradation gene polymorphisms in moderating the effects of food additives on children’s ADHD symptoms. Am. J. Psychiatry. 2010, 167, 1108–1115. [Google Scholar] [CrossRef]
  60. Meza-Velazquez, R.; Lopez-Marquez, F.; Espinosa-Padilla, S.; Rivera-Guillen, M.; Avila-Hernandez, J.; Rosales-Gonzalez, M. Association of diamine oxidase and histamine N-methyltransferase polymorphisms with presence of migraine in a group of Mexican mothers of children with allergies. Neurologia 2017, 32, 500–507. [Google Scholar] [CrossRef]
  61. Marasovic-Susnjara, I.; Palada, V.; Marinovic-Terzic, I.; Mimica, N.; Marin, J.; Muck-Seler, D.; Mustapic, M.; Presecki, P.; Pivac, N.; Folnegovic-Smalc, V.; et al. No association between histamine N-methyltransferase functional polymorphism Thr105Ile and Alzheimer’s disease. Neurosci. Lett. 2011, 489, 119–121. [Google Scholar] [CrossRef] [PubMed]
  62. Chen, Y.; Cao, B.; Ou, R.; Wei, Q.; Chen, X.; Zhao, B.; Wu, Y.; Song, W.; Shang, H.F. Determining the Effect of the HNMT, STK39, and NMD3 Polymorphisms on the Incidence of Parkinson’s Disease, Amyotrophic Lateral Sclerosis, and Multiple System Atrophy in Chinese Populations. J. Mol. Neurosci. 2018, 64, 574–580. [Google Scholar] [CrossRef] [PubMed]
  63. Garcia-Martin, E.; Martinez, C.; Benito-Leon, J.; Calleja, P.; Diaz-Sanchez, M.; Pisa, D.; Alonso-Navarro, H.; Ayuso-Peralta, L.; Torrecilla, D.; Agundez, J.A.; et al. Histamine-N-methyl transferase polymorphism and risk for multiple sclerosis. Eur. J. Neurol. 2010, 17, 335–338. [Google Scholar] [CrossRef]
  64. Jimenez-Jimenez, F.J.; Garcia-Martin, E.; Alonso-Navarro, H.; Martinez, C.; Zurdo, M.; Turpin-Fenoll, L.; Millan-Pascual, J.; Adeva-Bartolome, T.; Cubo, E.; Navacerrada, F.; et al. Thr105Ile (rs11558538) polymorphism in the histamine-1-methyl-transferase (HNMT) gene and risk for restless legs syndrome. J. Neural. Transm. (Vienna) 2017, 124, 285–291. [Google Scholar] [CrossRef] [PubMed]
  65. Reuter, M.; Jeste, N.; Klein, T.; Hennig, J.; Goldman, D.; Enoch, M.A.; Oroszi, G. Association of THR105Ile, a functional polymorphism of histamine N-methyltransferase (HNMT), with alcoholism in German Caucasians. Drug Alcohol Depend. 2007, 87, 69–75. [Google Scholar] [CrossRef] [PubMed]
  66. Oroszi, G.; Enoch, M.A.; Chun, J.; Virkkunen, M.; Goldman, D. Thr105Ile, a functional polymorphism of histamine N-methyltransferase, is associated with alcoholism in two independent populations. Alcohol Clin. Exp. Res. 2005, 29, 303–309. [Google Scholar] [CrossRef] [PubMed]
  67. Kim, S.H.; Kang, Y.M.; Kim, S.H.; Cho, B.Y.; Ye, Y.M.; Hur, G.Y.; Park, H.S. Histamine N-methyltransferase 939A>G polymorphism affects mRNA stability in patients with acetylsalicylic acid-intolerant chronic urticaria. Allergy 2009, 64, 213–221. [Google Scholar] [CrossRef]
  68. Kellermayer, B.; Polgar, N.; Pal, J.; Banati, M.; Maasz, A.; Kisfali, P.; Hosszu, Z.; Juhasz, A.; Jensen, H.B.; Tordai, A.; et al. Association of myasthenia gravis with polymorphisms in the gene of histamine N-methyltransferase. Hum. Immunol. 2013, 74, 1701–1704. [Google Scholar] [CrossRef]
  69. Heidari, A.; Tongsook, C.; Najafipour, R.; Musante, L.; Vasli, N.; Garshasbi, M.; Hu, H.; Mittal, K.; McNaughton, A.J.; Sritharan, K.; et al. Mutations in the histamine N-methyltransferase gene, HNMT, are associated with nonsyndromic autosomal recessive intellectual disability. Hum. Mol. Genet. 2015, 24, 5697–5710. [Google Scholar] [CrossRef]
  70. Tongsook, C.; Niederhauser, J.; Kronegger, E.; Straganz, G.; Macheroux, P. Leucine 208 in human histamine N-methyltransferase emerges as a hotspot for protein stability rationalizing the role of the L208P variant in intellectual disability. Biochim. Biophys. Acta Mol. Basis Dis. 2017, 1863, 188–199. [Google Scholar] [CrossRef]
  71. Van Wamelen, D.J.; Shan, L.; Aziz, N.A.; Anink, J.J.; Bao, A.M.; Roos, R.A.; Swaab, D.F. Functional increase of brain histaminergic signaling in Huntington’s disease. Brain Pathol. 2011, 21, 419–427. [Google Scholar] [CrossRef] [PubMed]
  72. Shan, L.; Bossers, K.; Luchetti, S.; Balesar, R.; Lethbridge, N.; Chazot, P.L.; Bao, A.M.; Swaab, D.F. Alterations in the histaminergic system in the substantia nigra and striatum of Parkinson’s patients: A postmortem study. Neurobiol. Aging 2012, 33, 1488 e1–1488 e13. [Google Scholar] [CrossRef] [PubMed]
  73. Kim, S.H.; Krapfenbauer, K.; Cheon, M.S.; Fountoulakis, M.; Cairns, N.J.; Lubec, G. Human brain cytosolic histamine-N-methyltransferase is decreased in Down syndrome and increased in Pick’s disease. Neurosci. Lett. 2002, 321, 169–172. [Google Scholar] [CrossRef]
  74. Shan, L.; Bossers, K.; Unmehopa, U.; Bao, A.M.; Swaab, D.F. Alterations in the histaminergic system in Alzheimer’s disease: A postmortem study. Neurobiol. Aging 2012, 33, 2585–2598. [Google Scholar] [CrossRef]
  75. Shan, L.; Qi, X.R.; Balesar, R.; Swaab, D.F.; Bao, A.M. Unaltered histaminergic system in depression: A postmortem study. J. Affect. Disord. 2013, 146, 220–223. [Google Scholar] [CrossRef]
  76. Duch, D.S.; Bowers, S.W.; Nichol, C.A. Elevation of brain histamine levels by diaminopyrimidine inhibitors of histamine N-methyl transferase. Biochem. Pharmacol. 1978, 27, 1507–1509. [Google Scholar] [CrossRef]
  77. Duch, D.S.; Edelstein, M.P.; Nichol, C.A. Inhibition of histamine-metabolizing enzymes and elevation of histamine levels in tissues by lipid-soluble anticancer folate antagonists. Mol. Pharmacol. 1980, 18, 100–104. [Google Scholar]
  78. Hough, L.B.; Khandelwal, J.K.; Green, J.P. Inhibition of brain histamine metabolism by metoprine. Biochem. Pharmacol. 1986, 35, 307–310. [Google Scholar] [CrossRef]
  79. Malmberg-Aiello, P.; Lamberti, C.; Ghelardini, C.; Giotti, A.; Bartolini, A. Role of histamine in rodent antinociception. Br. J. Pharmacol. 1994, 111, 1269–1279. [Google Scholar] [CrossRef][Green Version]
  80. Lecklin, A.; Tuomisto, L. Inhibition of histamine catabolism suppresses fat intake but not the intake of carbohydrates and protein. Inflamm. Res. 2002, 51, S53–S54. [Google Scholar]
  81. Nishibori, M.; Itoh, Y.; Oishi, R.; Saeki, K. Mechanism of the central hyperglycemic action of histamine in mice. J. Pharmacol. Exp. Ther. 1987, 241, 582–586. [Google Scholar]
  82. Malmberg-Aiello, P.; Ipponi, A.; Bartolini, A.; Schunack, W. Antiamnesic effect of metoprine and of selective histamine H(1) receptor agonists in a modified mouse passive avoidance test. Neurosci. Lett. 2000, 288, 1–4. [Google Scholar] [CrossRef]
  83. Yawata, I.; Tanaka, K.; Nakagawa, Y.; Watanabe, Y.; Murashima, Y.L.; Nakano, K. Role of histaminergic neurons in development of epileptic seizures in EL mice. Brain Res. Mol. Brain Res. 2004, 132, 13–17. [Google Scholar] [CrossRef] [PubMed]
  84. Kamei, C. Involvement of central histamine in amygdaloid kindled seizures in rats. Behav. Brain Res. 2001, 124, 243–250. [Google Scholar] [CrossRef]
  85. Yokoyama, H.; Onodera, K.; Maeyama, K.; Yanai, K.; Iinuma, K.; Tuomisto, L.; Watanabe, T. Histamine levels and clonic convulsions of electrically-induced seizure in mice: The effects of alpha-fluoromethylhistidine and metoprine. Naunyn Schmiedebergs Arch. Pharmacol. 1992, 346, 40–45. [Google Scholar] [CrossRef]
  86. Kitanaka, J.; Kitanaka, N.; Hall, F.S.; Uhl, G.R.; Takemura, M. Brain Histamine N-Methyltransferase As a Possible Target of Treatment for Methamphetamine Overdose. Drug Target Insights 2016, 10, 1–7. [Google Scholar] [CrossRef]
  87. Cavallito, J.C.; Nichol, C.A.; Brenckman, W.D., Jr.; Deangelis, R.L.; Stickney, D.R.; Simmons, W.S.; Sigel, C.W. Lipid-soluble inhibitors of dihydrofolate reductase. I. Kinetics, tissue distribution, and extent of metabolism of pyrimethamine, metoprine, and etoprine in the rat, dog, and man. Drug Metab. Dispos. 1978, 6, 329–337. [Google Scholar] [PubMed]
  88. Hamrell, M.R. Inhibition of dihydrofolate reductase and cell growth by antifolates in a methotrexate-resistant cell line. Oncology 1984, 41, 343–348. [Google Scholar] [CrossRef]
  89. Beaven, M.A.; Shaff, R.E. New inhibitors of histamine-N-methyltransferase. Biochem. Pharmacol. 1979, 28, 183–188. [Google Scholar] [CrossRef]
  90. Lin, J.S.; Sakai, K.; Jouvet, M. Evidence for histaminergic arousal mechanisms in the hypothalamus of cat. Neuropharmacology 1988, 27, 111–122. [Google Scholar] [CrossRef]
  91. Malmberg-Aiello, P.; Lamberti, C.; Ipponi, A.; Hanninen, J.; Ghelardini, C.; Bartolini, A. Effects of two histamine-N-methyltransferase inhibitors, SKF 91488 and BW 301 U, in rodent antinociception. Naunyn Schmiedebergs Arch. Pharmacol. 1997, 355, 354–360. [Google Scholar] [CrossRef] [PubMed]
  92. Fiorenza, N.G.; Rosa, J.; Izquierdo, I.; Myskiw, J.C. Modulation of the extinction of two different fear-motivated tasks in three distinct brain areas. Behav. Brain Res. 2012, 232, 210–216. [Google Scholar] [CrossRef] [PubMed]
  93. Horton, J.R.; Sawada, K.; Nishibori, M.; Cheng, X. Structural basis for inhibition of histamine N-methyltransferase by diverse drugs. J. Mol. Biol. 2005, 353, 334–344. [Google Scholar] [CrossRef] [PubMed]
  94. Tachibana, T.; Taniguchi, S.; Imamura, S.; Fujiwara, M.; Hayashi, H. Effects of drugs on the activity of histamine-N-methyltransferase from guinea pig skin. Biochem. Pharmacol. 1988, 37, 2872–2876. [Google Scholar] [PubMed]
  95. Cumming, P.; Reiner, P.B.; Vincent, S.R. Inhibition of rat brain histamine-N-methyltransferase by 9-amino-1,2,3,4-tetrahydroacridine (THA). Biochem. Pharmacol. 1990, 40, 1345–1350. [Google Scholar] [CrossRef]
  96. Nomura, H.; Mizuta, H.; Norimoto, H.; Masuda, F.; Miura, Y.; Kubo, A.; Kojima, H.; Ashizuka, A.; Matsukawa, N.; Baraki, Z.; et al. Central Histamine Boosts Perirhinal Cortex Activity and Restores Forgotten Object Memories. Biol. Psychiatry 2018. [Google Scholar] [CrossRef]
  97. Sasahara, I.; Fujimura, N.; Nozawa, Y.; Furuhata, Y.; Sato, H. The effect of histidine on mental fatigue and cognitive performance in subjects with high fatigue and sleep disruption scores. Physiol. Behav. 2015, 147, 238–244. [Google Scholar] [CrossRef] [PubMed][Green Version]
  98. Malmlof, K.; Zaragoza, F.; Golozoubova, V.; Refsgaard, H.H.; Cremers, T.; Raun, K.; Wulff, B.S.; Johansen, P.B.; Westerink, B.; Rimvall, K. Influence of a selective histamine H3 receptor antagonist on hypothalamic neural activity, food intake and body weight. Int. J. Obes. (Lond.) 2005, 29, 1402–1412. [Google Scholar] [CrossRef][Green Version]
  99. Morisset, S.; Traiffort, E.; Arrang, J.M.; Schwartz, J.C. Changes in histamine H3 receptor responsiveness in mouse brain. J. Neurochem. 2000, 74, 339–346. [Google Scholar] [CrossRef]
  100. Garcia-Martin, E.; Garcia-Menaya, J.; Sanchez, B.; Martinez, C.; Rosendo, R.; Agundez, J.A. Polymorphisms of histamine-metabolizing enzymes and clinical manifestations of asthma and allergic rhinitis. Clin. Exp. Allergy 2007, 37, 1175–1182. [Google Scholar] [CrossRef]
  101. Sharma, S.; Mann, D.; Singh, T.P.; Ghosh, B. Lack of association of histamine-N-methyltransferase (HNMT) polymorphisms with asthma in the Indian population. J. Hum. Genet. 2005, 50, 611–617. [Google Scholar] [CrossRef] [PubMed]
  102. Deindl, P.; Peri-Jerkan, S.; Deichmann, K.; Niggemann, B.; Lau, S.; Sommerfeld, C.; Sengler, C.; Muller, S.; Wahn, U.; Nickel, R.; et al. No association of histamine-N-methyltransferase polymorphism with asthma or bronchial hyperresponsiveness in two German pediatric populations. Pediatr. Allergy Immunol. 2005, 16, 40–42. [Google Scholar] [CrossRef] [PubMed]
  103. Szczepankiewicz, A.; Breborowicz, A.; Sobkowiak, P.; Popiel, A. Polymorphisms of two histamine-metabolizing enzymes genes and childhood allergic asthma: A case control study. Clin. Mol. Allergy 2010, 8, 14. [Google Scholar] [CrossRef] [PubMed]
Figure 1. Neurotransmission and termination of histaminergic nervous system. Histidine decarboxylase (Hdc) synthesises histamine from histidine. Histamine is stored in synaptic vesicles via vesicular monoamine transporter 2 (Vmat2). Upon stimulation, histamine is released to extraneuronal spaces. Histamine exerts its effects through interactions with postsynaptic histamine h1 receptor (H1R) and H2R, and presynaptic H3R. Extracellular histamine is transported via organic cation transporter 3 (Oct3) and plasma membrane monoamine transporter (Pmat). Finally, histamine is metabolised by histamine N-methyltransferase (Hnmt) [19,32]. Although previous studies have shown the importance of astrocytes for histamine clearance in the CNS [18], several reports suggest the involvement of neurons in histamine clearance [33,34].
Figure 1. Neurotransmission and termination of histaminergic nervous system. Histidine decarboxylase (Hdc) synthesises histamine from histidine. Histamine is stored in synaptic vesicles via vesicular monoamine transporter 2 (Vmat2). Upon stimulation, histamine is released to extraneuronal spaces. Histamine exerts its effects through interactions with postsynaptic histamine h1 receptor (H1R) and H2R, and presynaptic H3R. Extracellular histamine is transported via organic cation transporter 3 (Oct3) and plasma membrane monoamine transporter (Pmat). Finally, histamine is metabolised by histamine N-methyltransferase (Hnmt) [19,32]. Although previous studies have shown the importance of astrocytes for histamine clearance in the CNS [18], several reports suggest the involvement of neurons in histamine clearance [33,34].
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Figure 2. Enzymatic activity of histamine N-methyltransferase. Histamine N-methyltransferase catalyses the transfer of a methyl group from S-adenosyl-l-methionine to histamine, yielding Nτ-methylhistamine and S-adenosyl-l-homocysteine.
Figure 2. Enzymatic activity of histamine N-methyltransferase. Histamine N-methyltransferase catalyses the transfer of a methyl group from S-adenosyl-l-methionine to histamine, yielding Nτ-methylhistamine and S-adenosyl-l-homocysteine.
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Figure 3. Structures of HNMT inhibitors. Structures of typical HNMT inhibitors amodiaquine, tacrine, etoprine, metoprine, chloroquine, quinacrine, dimaprit, and SKF91488 are depicted.
Figure 3. Structures of HNMT inhibitors. Structures of typical HNMT inhibitors amodiaquine, tacrine, etoprine, metoprine, chloroquine, quinacrine, dimaprit, and SKF91488 are depicted.
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Table 1. Basic data of human, mouse, rat, and guinea pig histamine N-methyltransferase (HNMT).
Table 1. Basic data of human, mouse, rat, and guinea pig histamine N-methyltransferase (HNMT).
Human [39,48]Mouse [49]Rat [50]Guinea pig [51]
Cloning year1994200119922001
Chromosome2q22.12A33p13N.D.
Amino acid292 aa295 aa292 aa295 aa
Homology * 83%83%81%
Km (µM)Histamine13–205.37.1N.D.
SAM2.0–6.25.86.3N.D.
* Homology to human HNMT protein; aa—amino acids; Km—Michaelis constant; N.D.—not determined; SAM—S-adenosyl-L-methionine.
Table 2. Human HNMT mutations and brain diseases.
Table 2. Human HNMT mutations and brain diseases.
AuthorsYearSNPEnzymatic ActivityDiseaseAssociationNote
Jimenez-Jimenez et al. [58]2016C314T
(Thr105Ile)
(rs11558538)
T allele carrier
DecreasedParkinson’s disease (PD)Diagnostic OR 0.61Caucasians and Asians
Yang et al. [57]2015C314T
(Thr105Ile)
(rs11558538)
CT hetero allele
DecreasedPDOR 0.53Han Chinese
Palada et al. [56]2012C314T
(Thr105Ile)
(rs11558538)
DecreasedPDThr105 frequency was associated with PDCaucasians
Yang et al. [57]2015C314T
(Thr105Ile)
(rs11558538)
CT hetero allele
DecreasedSchizophreniaOR 0.499Han Chinese
Stevenson et al. [59]2010C314T
(Thr105Ile)
(rs11558538)
T allele
DecreasedADHDDecreased hyperactivityFood additives stimulation
Stevenson et al. [59]2010A939G (3′-UTR)
(rs1050891)
G allele
Increased (mRNA stability)ADHDDecreased hyperactivityFood additives stimulation
Meza-Velazquez et al. [60]2017C314T
(Thr105Ile)
(rs11558538)
CT hetero allele
DecreasedMigraineOR 37.10Migraine-related disability Grade IV
Kellermayer et al. [68]2017A939G
(3′-UTR)
(rs1050891)
G allele
Increased (mRNA stability)Myasthenia gravis (MG)OR 0.52Anti-Titin positive MG
Heidari et al. [69]2015G179A
(Gly60Asp)
(rs758252808)
DecreasedIntellectual disability (AR)Low IQTurkish
Heidari et al. [69]2015T632C
(Leu208Pro)
(rs745756308)
DecreasedIntellectual disability (AR)Low IQKurdish
Marasovic-Susnjara et al. [61]2011C314T
(Thr105Ile)
(rs11558538)
DecreasedAlzheimer’s diseaseNo association
Chen et al. [62]2018C314
(Thr105Ile)
(rs11558538)
DecreasedAmyotrophic Lateral SclerosisNo association
Reuter et al. [65]2007C314T
(Thr105Ile)
(rs11558538)
DecreasedAlcoholismNo associationGerman Caucasians
Oroszi et al. [66]2006C314T
(Thr105Ile)
(rs11558538)
DecreasedAlcoholismThr105 frequency was associated with alcoholism.Finnish Caucasians, Plains Indians
Gracia-Martin et al. [63]2010C314T
(Thr105Ile)
(rs11558538)
DecreasedMultiple sclerosisNo association
Jimenez-Jimenez et al. [64]2016C314T
(Thr105Ile)
(rs11558538)
DecreasedRestless legs syndrome (RLS)No association
(TT allele might be a risk factor for early onset of RLS)
PD–Parkinson’s disease; OR–Odds ratio; ADHD–Attention deficit hyperactivity disorder; IQ–Intelligence quotient; SNP—single nucleotide polymorphism.
Table 3. Characteristics of HNMT inhibitors.
Table 3. Characteristics of HNMT inhibitors.
InhibitorsM.W.IC50 or KiInhibition PatternNote
Amodiaquine355.86Ki 18.6 nM (recombinant hHNMT) [93]
IC50 400 nM (recombinant hHNMT) [39]
MixedAn antimalarial drug
Chloroquine319.88IC50 600 nM (guinea pig skin) [94]
IC50 12.6, 22.0 19.0 and 21.7 µM (human liver, renal cortex, brain and colon) [44]
Competitive to histamineAn antimalarial drug
Dimaprit161.27Ki 8 µM (rat kidney) [89]
Ki 7–9 µM (guinea pig brain) [89]
Noncompetitive to histamineH2R agonist
Etoprine283.16Ki 760 nM (rat brain) [76]N.D.Dihydrofolate reductase inhibitor
Metoprine269.13Ki 100 nM (rat brain) [76]
Ki 91 nM (recombinant hHNMT) [93]
Competitive to histamineDihydrofolate reductase inhibitor
Quinacrine399.96IC50 160 nM (guinea pig skin) [94]
Ki 450 nM (recombinant hHNMT) [52]
Competitive to histamine An antimalarial drug
SKF91488175.29Ki 0.9–1.6 µM (rat kidney) [89]
Ki 1.85 µM (recombinant rat HNMT) [50]
Ki 3 µM (guinea pig brain) [89]
Noncompetitive to histaminePoor BBB permeability
Tacrine198.27Ki 38.2 nM (recombinant hHNMT) [93]
Ki 35 nM (rat kidney) [95]
Competitive to histamineAcetylcholinesterase inhibitor
IC50—half maximal inhibitory concentration; Ki—inhibitory constant; M.W.—molecular weight; N.D.—not determined.
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