Alternative titles; symbols
HGNC Approved Gene Symbol: HRH1
Cytogenetic location: 3p25.3 Genomic coordinates (GRCh38): 3:11,137,238-11,263,557 (from NCBI)
The HRH1 gene encodes a G protein-coupled receptor that mediates diverse neuronal and peripheral actions of histamine.
Histamine is a ubiquitous messenger molecule released from mast cells, enterochromaffin-like cells, and neurons. Its various actions are mediated by 3 pharmacologically defined receptors termed the H1, H2 (HRH2; 142703), and H3 (HRH3; 604525) receptors. The H1 receptor was the first member of this family to be pharmacologically defined with the design of selective antagonists, the 'antihistamines,' which are used to treat allergic and inflammatory reactions. The H1 receptor is expressed by various peripheral tissues, such as smooth muscle, and by neurons in the brain, where histamine may be involved in the control of wakefulness, mood, and hormone secretion. Yamashita et al. (1991) cloned a bovine H1 receptor cDNA and established its nucleotide sequence. Its homology with the corresponding sequence of other receptors confirmed that it belongs to the superfamily of receptors coupled with G proteins with 7 putative transmembrane domains.
In addition to their expression in neuronal, gastric, and muscular tissue, the G protein-coupled receptors HRH1 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.
Le Coniat et al. (1994) assigned the human histamine H1-receptor gene to chromosome 3 by Southern blot analysis of human/hamster somatic cell hybrids. The assignment was confirmed and refined to 3p21-p14 by isotopic in situ hybridization. Inoue et al. (1996) concluded that the mouse histamine H1 receptor gene (Hrh1) is a single locus and is located in the central portion of mouse chromosome 6 in a region of homology with human chromosome 3p.
Crystal Structure
Shimamura et al. (2011) showed the crystal structure of the H1R complex with doxepin, a first-generation H1R antagonist. Doxepin sits deep in the ligand-binding pocket and directly interacts with trp428, a highly conserved key residue in G protein-coupled receptor activation. This well-conserved pocket with mostly hydrophobic nature contributes to the low selectivity of the first-generation compounds. The pocket is associated with an anion-binding region occupied by a phosphate ion. Docking of various second-generation H1R antagonists revealed that the unique carboxyl group present in this class of compounds interacts with lys191 and/or lys179, both of which form part of the anion-binding region. This region is not conserved in other aminergic receptors, demonstrating how minor differences in receptors lead to pronounced selectivity differences with small molecules.
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 immunoglobulins 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.
Ma et al. (2002) noted that pertussis toxin (PTX) elicits a range of responses in mice, including sensitization to vasoactive amines (VAAS) and increased vascular permeability subsequent to PTX-induced changes in vascular endothelial cells. Susceptible mouse strains die from hypotensive and hypovolemic shock on vasoactive amine challenge, whereas resistant strains do not. This hypersensitivity is controlled by an autosomal dominant locus, designated Bphs, localized to mouse chromosome 6. Using positional cloning, Ma et al. (2002) linked the Bphs locus to Hrh1. Mice lacking Hrh1 were protected from VAAS hypersensitivity, as well as from experimental allergic encephalomyelitis and experimental autoimmune orchitis. Sequence analysis showed that leu263-to-pro (L263P), met313-to-val (M313V), and ser331-to-pro (S331P) polymorphisms were associated with resistance to vasoactive amine challenge. The authors concluded that these Hrh1 alleles control both the autoimmune T-cell and vascular responses regulated by histamine after PTX sensitization.
Huang et al. (2006) reported that Hrh1-knockout mice demonstrated alterations in the regulation of sleep transitions from nonrapid eye movement sleep to wakefulness. Unlike wildtype mice, Hrh1-knockout mice did not demonstrate wakefulness after administration of an Hrh3 antagonist. The findings suggested that Hrh1 is involved in the regulation of sleep transition states and that Hrh1 mediates the arousal effects of Hrh3 antagonists.
Using a murine asthma model, Bryce et al. (2006) observed enhanced Th2 cytokine production in spleens but not lungs of H1r-deficient mice. Airway inflammation, goblet cell metaplasia, and airway hyperresponsiveness were reduced in these mice, but they could be restored by intranasal administration of IL4 or IL13. The absence of lung inflammation was attributable to defective T-cell trafficking, as the authors identified histamine as a chemotactic factor for T lymphocytes. Blockade of H1r, but not of H2r, ablated the migratory response in vitro. Bryce et al. (2006) concluded that histamine and H1R have a role in promoting migration of Th2 cells into sites of allergen exposure.
In mouse hippocampal slices and intact animals, Kim et al. (2007) found that atypical antipsychotic drugs, including clozapine and olanzapine, markedly increased phosphorylation and activation of hypothalamic AMPK (see, e.g., PRKAA1; 602739) in proportion to their affinities for Hrh1. In contrast, clozapine showed no effect on AMPK activation in Hrh1-knockout mice compared to wildtype. The findings suggested that orexigenic atypical antipsychotics act via Hrh1 and AMPK.
Noubade et al. (2007) found that Cd4 (186940)-positive T cells from H1r-deficient mice exhibited lower Ifng production, enhanced Il4 production, impaired activation of p38 (MAPK14; 600289), and no changes in Il17 (see 603149) and Il2 (147680) production or cellular proliferation. Transgenic reexpression of H1r in Cd4-positive T cells of H1r-deficient mice restored Ifng production as well as susceptibility to EAE. Addition of histamine to culture medium resulted in binding of histamine to H1r and p38 phosphorylation, followed by Ifng production, in wildtype Cd4-positive T cells. Noubade et al. (2007) proposed that targeting H1R may be useful early in the treatment of some autoimmune diseases, including multiple sclerosis (126200).
Bryce, P. J., Mathias, C. B., Harrison, K. L., Watanabe, T., Geha, R. S., Oettgen, H. C. The H1 histamine receptor regulates allergic lung responses. J. Clin. Invest. 116: 1624-1632, 2006. [PubMed: 16680192] [Full Text: https://doi.org/10.1172/JCI26150]
Huang, Z.-L., Mochizuki, T., Qu, W.-M., Hong, Z.-Y., Watanabe, T., Urade, Y., Hayaishi, O. Altered sleep-wake characteristics and lack of arousal response to H3 receptor antagonist in histamine H1 receptor knockout mice. Proc. Nat. Acad. Sci. 103: 4687-4692, 2006. [PubMed: 16537376] [Full Text: https://doi.org/10.1073/pnas.0600451103]
Inoue, I., Taniuchi, I., Kitamura, D., Jenkins, N. A., Gilbert, D. J., Copeland, N. G., Watanabe, T. Characteristics of the mouse genomic histamine H1 receptor gene. Genomics 36: 178-181, 1996. [PubMed: 8812432] [Full Text: https://doi.org/10.1006/geno.1996.0441]
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]
Kim, S. F., Huang, A. S., Snowman, A. M., Teuscher, C., Snyder, S. H. Antipsychotic drug-induced weight gain mediated by histamine H1 receptor-linked activation of hypothalamic AMP-kinase. Proc. Nat. Acad. Sci. 104: 3456-3459, 2007. [PubMed: 17360666] [Full Text: https://doi.org/10.1073/pnas.0611417104]
Le Coniat, M., Traiffort, E., Ruat, M., Arrang, J.-M., Berger, R. Chromosomal localization of the human histamine H1-receptor gene. Hum. Genet. 94: 186-188, 1994. [PubMed: 8045566] [Full Text: https://doi.org/10.1007/BF00202867]
Ma, R. Z., Gao, J., Meeker, N. D., Fillmore, P. D., Tung, K. S. K., Watanabe, T., Zachary, J. F., Offner, H., Blankenhorn, E. P., Teuscher, C. Identification of Bphs, an autoimmune disease locus, as histamine receptor H-1. Science 297: 620-623, 2002. [PubMed: 12142541] [Full Text: https://doi.org/10.1126/science.1072810]
Noubade, R., Milligan, G., Zachary, J. F., Blankenhorn, E. P., del Rio, R., Rincon, M., Teuscher, C. Histamine receptor H1 is required for TCR-mediated p38 MAPK activation and optimal IFN-gamma production in mice. J. Clin. Invest. 117: 3507-3518, 2007. [PubMed: 17965772] [Full Text: https://doi.org/10.1172/JCI32792]
Shimamura, T. Shiroishi, M., Weyand, S., Tsujimoto, H., Winter, G., Katritch, V., Abagyan, R., Cherezov, V., Liu, W., Han, G. W., Kobayashi, T., Stevens, R. C., Iwata, S. Structure of the human histamine H1 receptor complex with doxepin. Nature 475: 65-70, 2011. [PubMed: 21697825] [Full Text: https://doi.org/10.1038/nature10236]
Yamashita, M., Fukui, H., Sugama, K., Horio, Y., Ito, S., Mizuguchi, H., Wada, H. Expression cloning of a cDNA encoding the bovine histamine H1 receptor. Proc. Nat. Acad. Sci. 88: 11515-11519, 1991. [PubMed: 1722337] [Full Text: https://doi.org/10.1073/pnas.88.24.11515]