HGNC Approved Gene Symbol: HRH2
Cytogenetic location: 5q35.2 Genomic coordinates (GRCh38): 5:175,658,071-175,710,756 (from NCBI)
The HRH2 gene encodes a G protein-coupled receptor that mediates the effects of histamine.
Gantz et al. (1991) cloned a gene in the dog that encodes the H2 subclass of histamine receptors. Histamine is one of the major determinants of gastric acid secretion. It exerts its stimulating effect on gastric parietal cells through an H2 subclass of receptor coupled via a guanine nucleotide-binding protein (G protein) to activation of adenylate cyclase and production of cAMP. Antagonism of the action of histamine at this receptor is the basis for the large pharmaceutical market for treatment of acid-peptic disorders of the gastrointestinal tract. Gantz et al. (1991) used synthetic oligonucleotides complementary to the DNA encoding the transmembrane regions of known G protein-linked receptors as primers for the polymerase chain reaction (PCR). Gantz et al. (1991) used PCR with oligonucleotide primers based on the nucleotide sequence of the canine HRH2 gene to clone its human homolog.
In addition to their expression in neuronal, gastric, and muscular tissue, the G protein-coupled receptors HRH1 (600167) and HRH2 are also expressed on T-helper lymphocytes and trigger different intracellular events upon activation. Using flow cytometric analysis, Jutel et al. (2001) demonstrated that histamine binds more strongly to Th1 than to Th2 cells. Flow cytometry and RT-PCR analysis showed that HRH1 is predominantly expressed on Th1 cells in an IL3 (147740)-upregulatable manner, while HRH2 is predominant on Th2 cells. Stimulation of naive, CD45RA+ (see 151460) T cells with IL12 (161560) resulted in preferential expression of HRH1, but stimulation with IL4 (147780) resulted in suppressed expression of HRH1, demonstrating that mature CD45RO+ Th1 and Th2 lymphocytes preferentially but not exclusively express HRH1 and HRH2, and that HRH1 and HRH2 are regulated by cytokines present in the immune environment. Histamine stimulation of Th1 cells resulted in significant calcium flux that could be blocked by an HRH1 antagonist, while stimulation of Th2 cells led to cAMP formation that could be blocked by an HRH2, but not an HRH1, antagonist. Furthermore, histamine enhanced Th1 but inhibited Th2 responses to anti-CD3. Histamine also enhanced peripheral blood mononuclear cell responses in sensitized individuals to a predominantly Th1 antigen, but suppressed responses to Th2 allergens.
Jutel et al. (2001) noted that HRH1 or HRH2 deletions are reported to result in abnormalities in the central nervous and gastrointestinal systems. Mice lacking Hrh1 have lower, whereas Hrh2-deficient mice have higher, percentages of Ifng (147570)-producing cells, compared to wildtype mice. Mice lacking either receptor tended to have a higher frequency of Il4-producing cells. Hrh1-deficient mice produced higher levels of antigen-specific IgG1 and IgE compared to wildtype mice, whereas levels of these Igs are reduced in Hrh2 knockout mice, indicating that Ifng-mediated suppression of IgE production predominated over the enhancement otherwise seen with enhanced IL4 or IL13 (147683) production. Jutel et al. (2001) concluded that histamine secreted from inflammation effector cells potently influences Th1 and Th2 responses as well as antibody isotypes as a regulatory loop in inflammatory reactions.
Gantz, I., Munzert, G., Tashiro, T., Schaffer, M., Wang, L., DelValle, J., Yamada, T. Molecular cloning of the human histamine H2 receptor. Biochem. Biophys. Res. Commun. 178: 1386-1392, 1991. [PubMed: 1714721] [Full Text: https://doi.org/10.1016/0006-291x(91)91047-g]
Gantz, I., Schaffer, M., DelValle, J., Logsdon, C., Campbell, V., Uhler, M., Yamada, T. Molecular cloning of a gene encoding the histamine H2 receptor. Proc. Nat. Acad. Sci. 88: 429-433, 1991. Note: Erratum: Proc. Nat. Acad. Sci. 88: 5937 only, 1991. [PubMed: 1703298] [Full Text: https://doi.org/10.1073/pnas.88.2.429]
Jutel, M., Watanabe, T., Klunker, S., Akdis, M., Thomet, O. A. R., Malolepszy, J., Zak-Nejmark, T., Koga, R., Kobayashi, T., Blaser, K., Akdis, C. A. Histamine regulates T-cell and antibody responses by differential expression of H1 and H2 receptors. Nature 413: 420-425, 2001. [PubMed: 11574888] [Full Text: https://doi.org/10.1038/35096564]