Histamine H2 receptor explained

H₂ receptors are a type of histamine receptor found in many parts of the anatomy of humans and other animals. They are positively coupled to adenylate cyclase via G_s alpha subunit. It is a potent stimulant of cAMP production, which leads to activation of protein kinase A. PKA functions to phosphorylate certain proteins, affecting their activity. The drug betazole is an example of a histamine H₂ receptor agonist.

Function

Histamine is a ubiquitous messenger molecule released from mast cells, enterochromaffin-like cells, and neurons. Its various actions are mediated by histamine receptors H₁, H₂, H₃ and H₄. The histamine receptor H₂ belongs to the rhodopsin-like family of G protein-coupled receptors. It is an integral membrane protein and stimulates gastric acid secretion. It also regulates gastrointestinal motility and intestinal secretion and is thought to be involved in regulating cell growth and differentiation.^[1] Histamine may play a role in penile erection.^[2]

Tissue distribution

Histamine H₂ receptors are expressed in the following tissues:

Peripheral tissues^{[3] [4]}

• Gastric parietal cells (oxyntic cells)
• Vascular smooth muscle
• Neutrophils
• Mast cells
• Heart
• Genitourinary system^[5] (uterus, bladder)

Central nervous system tissues

• Caudate–putamen
• Cerebral cortex (external layers)
• Hippocampal formation
• Dentate nucleus of the cerebellum

Physiological responses

Activation of the H₂ receptor results in the following physiological responses:

• Stimulation of gastric acid secretion (Target of anti-histaminergics (H₂ receptors) for peptic ulcer disease and GERD)
• Smooth muscle relaxation (Experimental histamine H₂ receptor agonist used for asthma and COPD)
• Inhibit antibody synthesis, T-cell proliferation and cytokine production
• Vasodilation – PKA activity causes phosphorylation of MLCK, decreasing its activity, resulting in MLC of myosin being dephosphorylated by MLCP and thus inhibiting contraction. The smooth muscle relaxation leads to vasodilation.^[6]
• Inhibition of neutrophil activation and chemotaxis

See also

• H₂-receptor antagonist
• Histamine H₁-receptor
• Histamine H₃-receptor
• Histamine H₄-receptor

Further reading

• Del Valle J, Gantz I . Novel insights into histamine H2 receptor biology . The American Journal of Physiology . 273 . 5 Pt 1 . G987-96 . Nov 1997 . 10.1152/ajpgi.1997.273.5.G987 . 9374694 .
• Gantz I, Munzert G, Tashiro T, Schäffer M, Wang L, DelValle J, Yamada T . Molecular cloning of the human histamine H2 receptor . Biochemical and Biophysical Research Communications . 178 . 3 . 1386–92 . Aug 1991 . 1714721 . 10.1016/0006-291X(91)91047-G . 2027.42/29176 . free .
• Vannier E, Dinarello CA . Histamine enhances interleukin (IL)-1-induced IL-6 gene expression and protein synthesis via H2 receptors in peripheral blood mononuclear cells . The Journal of Biological Chemistry . 269 . 13 . 9952–6 . Apr 1994 . 10.1016/S0021-9258(17)36975-2 . 7511596 . free .
• Smit MJ, Timmerman H, Alewijnse AE, Punin M, van den Nieuwenhof I, Blauw J, van Minnen J, Leurs R . Visualization of agonist-induced internalization of histamine H2 receptors . Biochemical and Biophysical Research Communications . 214 . 3 . 1138–45 . Sep 1995 . 7575521 . 10.1006/bbrc.1995.2404 .
• Nishi T, Koike T, Oka T, Maeda M, Futai M . Identification of the promoter region of the human histamine H2-receptor gene . Biochemical and Biophysical Research Communications . 210 . 2 . 616–23 . May 1995 . 7755641 . 10.1006/bbrc.1995.1703 .
• Traiffort E, Vizuete ML, Tardivel-Lacombe J, Souil E, Schwartz JC, Ruat M . The guinea pig histamine H2 receptor: gene cloning, tissue expression and chromosomal localization of its human counterpart . Biochemical and Biophysical Research Communications . 211 . 2 . 570–7 . Jun 1995 . 7794271 . 10.1006/bbrc.1995.1851 .
• Orange PR, Heath PR, Wright SR, Pearson RC . Allelic variations of the human histamine H2 receptor gene . NeuroReport . 7 . 7 . 1293–6 . May 1996 . 8817552 . 10.1097/00001756-199605170-00015 .
• Elenkov IJ, Webster E, Papanicolaou DA, Fleisher TA, Chrousos GP, Wilder RL . Histamine potently suppresses human IL-12 and stimulates IL-10 production via H2 receptors . Journal of Immunology . 161 . 5 . 2586–93 . Sep 1998 . 10.4049/jimmunol.161.5.2586 . 9725260 . 6034918 . free .
• Murakami H, Sun-Wada GH, Matsumoto M, Nishi T, Wada Y, Futai M . Human histamine H2 receptor gene: multiple transcription initiation and tissue-specific expression . FEBS Letters . 451 . 3 . 327–31 . May 1999 . 10371214 . 10.1016/S0014-5793(99)00618-3 . 33650873 . free .
• Wang LD, Wang M, Todisco A, Grand E, del Valle J . The human histamine H(2) receptor regulates c-jun and c-fos in a differential manner . American Journal of Physiology. Cell Physiology . 278 . 6 . C1246-55 . Jun 2000 . 10837353 . 10.1152/ajpcell.2000.278.6.c1246 .
• Suh BC, Lee H, Jun DJ, Chun JS, Lee JH, Kim KT . Inhibition of H2 histamine receptor-mediated cation channel opening by protein kinase C in human promyelocytic cells . Journal of Immunology . 167 . 3 . 1663–71 . Aug 2001 . 11466390 . 10.4049/jimmunol.167.3.1663 . 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 . 449–52 . Sep 2001 . 11603849 . 10.1007/PL00000269 . 28710647 .
• Shayo C, Fernandez N, Legnazzi BL, Monczor F, Mladovan A, Baldi A, Davio C . Histamine H2 receptor desensitization: involvement of a select array of G protein-coupled receptor kinases . Molecular Pharmacology . 60 . 5 . 1049–56 . Nov 2001 . 11641433 . 10.1124/mol.60.5.1049. 11336/31340 . 24358588 . free .
• Tanimoto A, Murata Y, Nomaguchi M, Kimura S, Arima N, Xu H, Hamada T, Sasaguri Y . Histamine increases the expression of LOX-1 via H2 receptor in human monocytic THP-1 cells . FEBS Letters . 508 . 3 . 345–9 . Nov 2001 . 11728449 . 10.1016/S0014-5793(01)03073-3 . 7257298 . free . 2001FEBSL.508..345T .
• 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 . 524–31 . Mar 2002 . 11898002 . 10.1067/mai.2002.121944 . free .
• Esbenshade TA, Kang CH, Krueger KM, Miller TR, Witte DG, Roch JM, Masters JN, Hancock AA . Differential activation of dual signaling responses by human H1 and H2 histamine receptors . Journal of Receptor and Signal Transduction Research . 23 . 1 . 17–31 . Feb 2003 . 12680587 . 10.1081/RRS-120018758 . 24392073 .

External links

• Web site: Histamine Receptors: H₂ . IUPHAR Database of Receptors and Ion Channels . International Union of Basic and Clinical Pharmacology .

Notes and References

1. Web site: Entrez Gene: HRH2 histamine receptor H2.
2. 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 .
3. Hill SJ, Ganellin CR, Timmerman H, Schwartz JC, Shankley NP, Young JM, Schunack W, Levi R, Haas HL . International Union of Pharmacology. XIII. Classification of histamine receptors . Pharmacological Reviews . 49 . 3 . 253–78 . Sep 1997 . 9311023 .
4. Web site: H₂ receptor. IUPHAR/BPS Guide to PHARMACOLOGY . International Union of Basic and Clinical Pharmacology . 20 March 2017 . Maguire JJ, Davenport AP . 29 November 2016 .
5. Bertaccini G, Coruzzi G . Extragastric H2-receptors . Journal of Clinical Gastroenterology . 5 Suppl 1 . 57–70 . 1983 . 6140284 . 10.1097/00004836-198312001-00006 . 24764785 .
6. Book: Walter F., PhD. Boron. Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders. 2005. 1-4160-2328-3 . Page 479