Histamine H1 receptor explained

The H₁ receptor is a histamine receptor belonging to the family of rhodopsin-like G-protein-coupled receptors. This receptor is activated by the biogenic amine histamine. It is expressed in smooth muscles, on vascular endothelial cells, in the heart, and in the central nervous system. The H₁ receptor is linked to an intracellular G-protein (G_q) that activates phospholipase C and the inositol triphosphate (IP3) signalling pathway. Antihistamines, which act on this receptor, are used as anti-allergy drugs. The crystal structure of the receptor has been determined (shown on the right/below)^[1] and used to discover new histamine H₁ receptor ligands in structure-based virtual screening studies.^[2]

Function

The expression of NF-κB, the transcription factor that regulates inflammatory processes, is promoted by the constitutive activity of the H₁ receptor as well as by agonists that bind at the receptor.^[3] H₁-antihistamines have been shown to attenuate NF-κB expression and mitigate certain inflammatory processes in associated cells.

Histamine may play a role in penile erection.^[4]

Neurophysiology

Histamine H₁ receptors are activated by endogenous histamine, which is released by neurons that have their cell bodies in the tuberomammillary nucleus of the hypothalamus. The histaminergic neurons of the tuberomammillary nucleus become active during the 'wake' cycle, firing at approximately 2 Hz; during slow wave sleep, this firing rate drops to approximately 0.5 Hz. Finally, during REM sleep, histaminergic neurons stop firing altogether. It has been reported that histaminergic neurons have the most wake-selective firing pattern of all known neuronal types.^[5]

The tuberomammillary nucleus is a histaminergic nucleus that strongly regulates the sleep-wake cycle.^[6] H₁-antihistamines that cross the blood–brain barrier inhibit H₁ receptor activity on neurons that project from the tuberomammillary nucleus. This action is responsible for the drowsiness effect associated with these drugs.

SARS-CoV-2

According to recent study the histamine receptor H1 can act as an alternative entry point for the SARS-CoV-2 virus to infect cells, in addition to the main receptor ACE2. HRH1 also synergistically enhanced hACE2-dependent viral entry by interacting with hACE2. Antihistamine drugs effectively prevent viral infection by competitively binding to HRH1, thereby disrupting the interaction between the spike protein and its receptor.^[7]

See also

• Antihistamine – Histamine receptor antagonists
• H₁-receptor antagonist
• Histamine H₂-receptor
• Histamine H₃-receptor
• Histamine H₄-receptor

Further reading

• Mitsuchashi M, Payan DG . Molecular and cellular analysis of histamine H1 receptors on cultured smooth muscle cells . Journal of Cellular Biochemistry . 40 . 2 . 183–192 . June 1989 . 2670975 . 10.1002/jcb.240400207 . 43161416 .
• Braman SS . Histamine receptors in the lung . New England and Regional Allergy Proceedings . 8 . 2 . 116–120 . 1987 . 2886904 . 10.2500/108854187778994446 .
• Hill SJ, Ganellin CR, Timmerman H, Schwartz JC, Shankley NP, Young JM, Schunack W, Levi R, Haas HL . 6 . International Union of Pharmacology. XIII. Classification of histamine receptors . Pharmacological Reviews . 49 . 3 . 253–278 . September 1997 . 9311023 .
• Holden CA, Chan SC, Norris S, Hanifin JM . Histamine induced elevation of cyclic AMP phosphodiesterase activity in human monocytes . Agents and Actions . 22 . 1–2 . 36–42 . October 1987 . 2891264 . 10.1007/BF01968814 . 23962587 .
• Moguilevsky N, Varsalona F, Noyer M, Gillard M, Guillaume JP, Garcia L, Szpirer C, Szpirer J, Bollen A . 6 . Stable expression of human H1-histamine-receptor cDNA in Chinese hamster ovary cells. Pharmacological characterisation of the protein, tissue distribution of messenger RNA and chromosomal localisation of the gene . European Journal of Biochemistry . 224 . 2 . 489–495 . September 1994 . 7925364 . 10.1111/j.1432-1033.1994.00489.x . free .
• Fukui H, Fujimoto K, Mizuguchi H, Sakamoto K, Horio Y, Takai S, Yamada K, Ito S . 6 . Molecular cloning of the human histamine H1 receptor gene . Biochemical and Biophysical Research Communications . 201 . 2 . 894–901 . June 1994 . 8003029 . 10.1006/bbrc.1994.1786 .
• Le Coniat M, Traiffort E, Ruat M, Arrang JM, Berger R . Chromosomal localization of the human histamine H1-receptor gene . Human Genetics . 94 . 2 . 186–188 . August 1994 . 8045566 . 10.1007/bf00202867 . 13583779 .
• De Backer MD, Gommeren W, Moereels H, Nobels G, Van Gompel P, Leysen JE, Luyten WH . Genomic cloning, heterologous expression and pharmacological characterization of a human histamine H1 receptor . Biochemical and Biophysical Research Communications . 197 . 3 . 1601–1608 . December 1993 . 8280179 . 10.1006/bbrc.1993.2662 .
• Hishinuma S, Young JM . Characteristics of the binding of [3H]-mepyramine to intact human U373 MG astrocytoma cells: evidence for histamine-induced H1-receptor internalisation . British Journal of Pharmacology . 116 . 6 . 2715–2723 . November 1995 . 8590995 . 1909113 . 10.1111/j.1476-5381.1995.tb17232.x .
• Max SI, Chowdhury BA, Fraser CM . Sequence analysis of the 5'-untranslated region of the human H1 histamine receptor-encoding gene . Gene . 171 . 2 . 309–310 . June 1996 . 8666296 . 10.1016/0378-1119(96)00036-4 .
• De Backer MD, Loonen I, Verhasselt P, Neefs JM, Luyten WH . Structure of the human histamine H1 receptor gene . The Biochemical Journal . 335 . Pt 3 . 663–670 . November 1998 . 9794809 . 1219830 . 10.1042/bj3350663 .
• Horváth BV, Szalai C, Mándi Y, László V, Radvány Z, Darvas Z, Falus A . Histamine and histamine-receptor antagonists modify gene expression and biosynthesis of interferon gamma in peripheral human blood mononuclear cells and in CD19-depleted cell subsets . Immunology Letters . 70 . 2 . 95–99 . November 1999 . 10569698 . 10.1016/S0165-2478(99)00126-1 .
• Wang KY, Arima N, Higuchi S, Shimajiri S, Tanimoto A, Murata Y, Hamada T, Sasaguri Y . 6 . Switch of histamine receptor expression from H2 to H1 during differentiation of monocytes into macrophages . FEBS Letters . 473 . 3 . 345–348 . May 2000 . 10818238 . 10.1016/S0014-5793(00)01560-X . 772640 .
• Oda T, Morikawa N, Saito Y, Masuho Y, Matsumoto S . Molecular cloning and characterization of a novel type of histamine receptor preferentially expressed in leukocytes . The Journal of Biological Chemistry . 275 . 47 . 36781–36786 . November 2000 . 10973974 . 10.1074/jbc.M006480200 . free .
• Brew OB, Sullivan MH . Localisation of mRNAs for diamine oxidase and histamine receptors H1 and H2, at the feto-maternal interface of human pregnancy . Inflammation Research . 50 . 9 . 449–452 . September 2001 . 11603849 . 10.1007/PL00000269 . 28710647 .
• Gutzmer R, Langer K, Lisewski M, Mommert S, Rieckborn D, Kapp A, Werfel T . Expression and function of histamine receptors 1 and 2 on human monocyte-derived dendritic cells . The Journal of Allergy and Clinical Immunology . 109 . 3 . 524–531 . March 2002 . 11898002 . 10.1067/mai.2002.121944 .
• Idzko M, la Sala A, Ferrari D, Panther E, Herouy Y, Dichmann S, Mockenhaupt M, Di Virgilio F, Girolomoni G, Norgauer J . 6 . Expression and function of histamine receptors in human monocyte-derived dendritic cells . The Journal of Allergy and Clinical Immunology . 109 . 5 . 839–846 . May 2002 . 11994709 . 10.1067/mai.2002.124044 .

External links

• Web site: Histamine Receptors: H₁ . IUPHAR Database of Receptors and Ion Channels . International Union of Basic and Clinical Pharmacology . 2006-07-20 . 2016-03-03 . https://web.archive.org/web/20160303192657/http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2303 . dead .

Notes and References

1. Shimamura T, Shiroishi M, Weyand S, Tsujimoto H, Winter G, Katritch V, Abagyan R, Cherezov V, Liu W, Han GW, Kobayashi T, Stevens RC, Iwata S . 6 . Structure of the human histamine H1 receptor complex with doxepin . Nature . 475 . 7354 . 65–70 . June 2011 . 21697825 . 3131495 . 10.1038/nature10236 .
2. de Graaf C, Kooistra AJ, Vischer HF, Katritch V, Kuijer M, Shiroishi M, Iwata S, Shimamura T, Stevens RC, de Esch IJ, Leurs R . 6 . Crystal structure-based virtual screening for fragment-like ligands of the human histamine H(1) receptor . Journal of Medicinal Chemistry . 54 . 23 . 8195–8206 . December 2011 . 22007643 . 3228891 . 10.1021/jm2011589 .
3. Canonica GW, Blaiss M . Antihistaminic, anti-inflammatory, and antiallergic properties of the nonsedating second-generation antihistamine desloratadine: a review of the evidence . The World Allergy Organization Journal . 4 . 2 . 47–53 . February 2011 . 23268457 . 3500039 . 10.1097/WOX.0b013e3182093e19 . The H1-receptor is a transmembrane protein belonging to the G-protein coupled receptor family. Signal transduction from the extracellular to the intracellular environment occurs as the GPCR becomes activated after binding of a specific ligand or agonist. A subunit of the G-protein subsequently dissociates and affects intracellular messaging including downstream signaling accomplished through various intermediaries such as cyclic AMP, cyclic GMP, calcium, and nuclear factor kappa B (NF-κB), a ubiquitous transcription factor thought to play an important role in immune-cell chemotaxis, proinflammatory cytokine production, expression of cell adhesion molecules, and other allergic and inflammatory conditions.1,8,12,30–32 ... For example, the H1-receptor promotes NF-κB in both a constitutive and agonist-dependent manner and all clinically available H1-antihistamines inhibit constitutive H1-receptor-mediated NF-κB production ...
   Importantly, because antihistamines can theoretically behave as inverse agonists or neutral antagonists, they are more properly described as H1-antihistamines rather than H1-receptor antagonists.15 .
4. Cará AM, Lopes-Martins RA, Antunes E, Nahoum CR, De Nucci G . The role of histamine in human penile erection . British Journal of Urology . 75 . 2 . 220–224 . February 1995 . 7850330 . 10.1111/j.1464-410x.1995.tb07315.x .
5. Passani MB, Lin JS, Hancock A, Crochet S, Blandina P . The histamine H3 receptor as a novel therapeutic target for cognitive and sleep disorders . Trends in Pharmacological Sciences . 25 . 12 . 618–625 . December 2004 . 15530639 . 10.1016/j.tips.2004.10.003 .
6. Book: Malenka RC, Nestler EJ, Hyman SE . Sydor A, Brown RY . Molecular Neuropharmacology: A Foundation for Clinical Neuroscience . 2009 . McGraw-Hill Medical . New York . 9780071481274 . 175–176 . 2nd . Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin . Within the brain, histamine is synthesized exclusively by neurons with their cell bodies in the tuberomammillary nucleus (TMN) that lies within the posterior hypothalamus. There are approximately 64000 histaminergic neurons per side in humans. These cells project throughout the brain and spinal cord. Areas that receive especially dense projections include the cerebral cortex, hippocampus, neostriatum, nucleus accumbens, amygdala, and hypothalamus.  ... While the best characterized function of the histamine system in the brain is regulation of sleep and arousal, histamine is also involved in learning and memory ... It also appears that histamine is involved in the regulation of feeding and energy balance..
7. https://journals.asm.org/doi/10.1128/mbio.01088-24