Histamine and histamine receptors


Histamine (HA) is a potent mediator in many physiological processes: it causes vasodilation or vasoconstriction, stimulates heart rate and contractility, and contraction of smooth muscles in the intestine and airways. It works as a neurotransmitter, immunomodulator, and regulator of haematopoiesis and angiogenesis.

Histamine neurons in the tuberomammillary nucleus of the posterior hypothalamus project their axons to the whole brain. Reduced histaminergic activity contributes to several neuropsychiatric disorders. In the development of central nervous system histamine regulates cell proliferation and differentiation (Molina-Hernández et al., 2012).

Synthesis and degradation

Histamine is mainly produced by histaminergic neurons, mast cells, basophils, and enterochromaffin-like cells in the gastric mucose. Cells produce histamine by decarboxylation of L-histidine, catalyzed by cytosolic histidine decarboxylase. Histamine is stored in cytoplasmic granules with serotonin, proteases, chemokines, etc. Degranulation in mast cells and basophils can be initiated and modulated by IgE-dependent stimuli and cytokines, substance P, etc.

In the brain, histamine is metabolized intracellularly by histamine-N-methyl transferase into 1-methylhistamine, which has much lower affinity to the histamine receptors. At least astrocytes are able to transport histamine via OCT3 and PMAT and degrade it. Then, MAO-B converts 1-methylhistamine into 1-methylimidazole4-acetaldehyde, which is further converted to 1-methylimidazole4-acetic acid by NADP-dependent aldehyde dehydrogenase.

Peripherally, histamine is metabolized by diamine oxidase into imidazole-4-acetaldehyde, which is further converted to imidazole-4-acetic acid (I4AA) by NAD-dependent aldehyde dehydrogenase. I4AA is a weak GABAA receptor agonist and GABAC receptor antagonist. I4AA is inactivated by imidazoleacetate-phosphoribosyldiphosphate ligase.

Histamine in foods can cause food poisoning. Fish contains high amount of histidine, which can be converted to histamine by bacteria.

Histamine receptors

Histamine binds to four G protein coupled receptors (GPCRs), H1R - H4R.

Histamine H1 receptor

Histamine H1 receptor (H1R) is expressed in various tissues, including the brain, smooth muscle of the vasculature and airways. In the brain, H1R has a role in memory, and regulation of sleep-arousal cycle. H1R is implicated in type I hypersensitivity allergic reactions. Allergens activate mast cells, which release histamine, which via binding to H1R causes vasodilation, vascular hyperpermeability, and oedema. Vascular leakage can be assessed with PET using for example labelled albumin or transferrin.

Antihistamines are inverse agonists of H1R, that is, they stabilize H1R into its inactive state. The first-generation antihistamines had high BBB permeability. The second-generation antihistamines have lower BBB permeability and higher receptor selectivity, but some side-effects still remain, including interaction with cardiac potassium channels. The occupancy of H1Rs in the brain caused by antihistamines can be studied with PET (Yanai et al., 2017).

H1R receptors in the brain can be assessed with PET using [11C]doxepin and [11C]pyrilamine, from which [11C]doxepin provides better image contrast and has lower radiometabolism (Funke et al., 2013). [11C]doxepin brain data can be analysed using compartmental models or late-scan-to-plasma ratio (Mochizuki et al., 2004a; 2004b). Cerebellum has been used as reference region input in SRTM and Logan plot analysis (Suzuki et al., 2005). [11C]pyrilamine brain data has been analysed using compartmental models and factor analysis (Szabo et al., 1993). [11C]doxepin binding in the brain was not found to be significantly affected by attentive calculation task or time of day (Shibuya et al., 2012).

Age correlates with H1R density (Yanai et al., 1992a and 1992b). [11C]doxepin binding was lower in the frontal cerebral cortex of subjects with depression than in control subjects (Kano et al., 2004; Yanai & Tashiro, 2007), and in the frontal and temporal cortex of AD patients (Higuchi et al., 2000). These imaging results are supported by post-mortem studies. H2R density is not reduced in AD patients (Perry et al., 1998). Schizophrenic patients have lower binding potential in the frontal and prefrontal cortex and in cingulate gyrus (Iwabuchi et al., 2005).

Binding potential of [11C]doxepin is significantly higher than that in male subjects in amygdala, hippocampus, medial prefrontal cortex, orbitofrontal cortex, and temporal cortex (Yoshizawa et al., 2009). Women with anorexia nervosa have higher BP in the amygdala and lentiform nucleus than control female subjects (Yoshizawa et al., 2009).

Histamine H2 receptor

Histamine H2 receptor (H2R) is ubiquitously expressed in various tissues, including the stomach, heart, and the brain. Gastric enterochromaffin-like cells respond to stimulation by gastrin and acetylcholine by releasing histamine, which binds to H2R on parietal cells of the stomach, inducing production of gastric acid; therefore H2R antagonists have been used to treat gastroesophageal reflux disease. H2R participates in regulation of food intake and glucose metabolism. H2R is involved in regulation of immune responses. In the brain, H2R modulates circadian rhythm and cognitive processes. In the heart, histamine produces a positive inotropic effect via H2Rs in the atrial and ventricular muscles. Both H1Rs and H2Rs are present in the smooth muscle of blood vessels, and activation of those by histamine causes vasoconstriction or vasodilation, respectively.

PET ligands for H2R are not yet available, because the developed compounds did not permeate the BBB. 125I-labelled nizatidine, H2R antagonist, might be useful for imaging peptic ulcer (Sanad et al., 2017).

Histamine H3 receptor

Histamine H3 receptor (H3R) is mainly expressed on neurons, as presynaptic auto- and heteroreceptor in the cerebral cortex and striatum, but also in the peripheral nervous system. H3R density is highest in the posterior hypothalamus where the histaminergic neuron cell bodies are located. In CNS, H3R inhibits the release of histamine, acetylcholine, noradrenaline, dopamine, and glutamate. Postsynaptic H3R expression may also be involved in regulation of signalling by other neurotransmitters. During myocardial ischemia, mast cells in the heart release histamine, fully activating local H3Rs. H3R inhibits the release of noradrenaline from sympathetic nerve terminals.

H3R has been implicated in learning and memory, stress and depression, food intake, sleep-wake regulation, pain, and ADHD. H3R antagonists may may useful in treatment of cognitive dysfunction, sleepiness, and narcolepsy.

H3 receptors can be studied with PET using [11C]GSK189254 (Plisson et al., 2009; Ashworth et al., 2010; Jucaite et al., 2013; Gallezot et al., 2017; Ghazanfari et al., 2022), [11C]MK-8278 (Van Laere et al., 2014), and [11C]TASP457 (Kimura et al., 2016; Ito et al., 2018). [11C]TASP457 can be used to assess pharmaceutical-induced occupancy of H3Rs (Kimura et al., 2022).

Histamine H4 receptor

Histamine H4 receptor (H4R) is a chemotactic receptor, mainly expressed on eosinophils, but also on mast cells, dendritic cells, and T cells. H4Rs are also expressed on the epithelium of the gastrointestinal tract. In asthma, H4R mediates the effects of histamine, while specific H1R and H2R antagonists do not have any effect. In the brain, histamine may restrain exacerbated microglial responses via H4Rs during inflammation (Ferreira et al., 2012). H4Rs are also expressed on neurons in the human brain cortex (Connelly et al., 2009).

Radioligands for H4R imaging with PET are being developed.

See also:


Fukudo S, Kano M, Sato Y, Muratsubaki T, Kanazawa M, Tashiro M, Yanai K. Histamine neuroimaging in stress-related disorders. Curr Top Behav Neurosci. 2022; 59: 113-129. doi: 10.1007/7854_2021_262.

Hattori Y, Seifert R (eds.): Histamine and Histamine Receptors in Health and Disease. Springer, 2017. ISBN 978-3-319-58194-1. doi: 10.1007/978-3-319-58194-1.

Panula P, Chazot PL, Cowart M, Gutzmer R, Leurs R, Liu WL, Stark H, Thurmond RL, Haas HL. International Union of Basic and Clinical Pharmacology. XCVIII. Histamine receptors. Pharmacol Rev. 2015; 67(3): 601-655. doi: 10.1124/pr.114.010249.

Thurmond RL (ed.): Histamine in Inflammation. Springer, 2010. ISBN: 978-1-4419-8055-7. doi: 10.1007/978-1-4419-8056-4.

Yanai K, Passani MB: The Functional Roles of Histamine Receptors. Springer Cham, 2022. doi: 10.1007/978-3-031-16997-7.

Yanai K, Tashiro M. The physiological and pathophysiological roles of neuronal histamine: an insight from human positron emission tomography studies. Pharmacol Ther. 2007; 113: 1-15. doi: 10.1016/j.pharmthera.2006.06.008.

Yanai K, Yoshikawa T, Yanai A, Nakamura T, Iida T, Leurs R, Tashiro M. The clinical pharmacology of non-sedating antihistamines. Pharmacol Ther. 2017; 178: 148-156. doi: 10.1016/j.pharmthera.2017.04.004.

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Updated at: 2024-05-29
Created at: 2018-09-12
Written by: Vesa Oikonen