| 1994 |
HRH1 (human RNA helicase 1) was identified as a human homolog of yeast Prp22, containing DEAH-box helicase motifs. HRH1 expression in a S. cerevisiae prp22 mutant partially rescued its temperature-sensitive phenotype. HRH1 contains an RS domain absent in Prp22, and this RS domain mediates interaction with SR protein family members both in vitro and in the yeast two-hybrid system, suggesting HRH1 is targeted to the spliceosome through this interaction. |
PCR cloning, yeast complementation assay, in vitro interaction assay, yeast two-hybrid |
Molecular and cellular biology |
High |
7935475
|
| 1996 |
HRH1 facilitates nuclear export of spliced mRNA by releasing it from the spliceosome. Dominant-negative HRH1++ mutants (dn-HRH1) stall on the spliceosome and prevent release of spliced RNA from the spliceosome in vitro. Expression of dn-HRH1 in mammalian cells inhibits splicing and causes nuclear export of unspliced pre-mRNA due to spliceosome recycling defects. The RS domain of HRH1 confers a nuclear localization signal and facilitates interaction with the spliceosome. |
Dominant-negative mutant expression, in vitro spliceosome release assay, mammalian cell transfection |
Genes & development |
High |
8608946
|
| 1993 |
The human histamine H1 receptor (HRH1/H1R) was cloned from a human genomic library; the 487-amino acid protein is a G-protein-coupled receptor. When expressed in COS-7 cells, it shows saturable binding of [3H]pyrilamine (KD ~1.2 nM) and mediates histamine-induced inositol phosphate formation that is inhibitable by pyrilamine, demonstrating coupling to the Gq/phospholipase C pathway. |
Genomic cloning, heterologous expression in COS-7 cells, radioligand binding assay, inositol phosphate formation assay |
Biochemical and biophysical research communications |
High |
8280179
|
| 1994 |
The human histamine H1 receptor gene is intron-lacking, encodes a 487-amino acid protein with GTP-binding protein-coupled receptor characteristics, and is mapped to chromosome 3p25 by fluorescence in situ hybridization. Northern blot analysis revealed tissue-specific expression with two mRNA species (3.0 and 3.5 kb) in peripheral tissues and only the 3.5-kb species in brain. |
Genomic cloning, Northern blot, FISH chromosomal mapping |
Biochemical and biophysical research communications |
High |
8003029
|
| 2004 |
GRK2 is the principal kinase mediating H1 histamine receptor (H1HR) desensitization in HEK293 cells. GRK2 overexpression promotes H1HR phosphorylation and completely inhibits inositol phosphate production. GRK2 regulates H1HR signaling through dual mechanisms: its kinase activity and its RGS function for Gαq/11. siRNA knockdown of endogenous GRK2 significantly increased histamine-promoted calcium flux, confirming endogenous GRK2 role. GRK5 had no significant effect. |
Overexpression of wild-type and mutant GRKs in HEK293 cells, phosphorylation assay, inositol phosphate assay, siRNA knockdown, calcium flux assay |
The Journal of biological chemistry |
High |
15542600
|
| 2005 |
Using site-directed mutagenesis and molecular modeling, Ser3.36 and Asn7.45 were identified as key residues linking histamine binding to receptor activation in the human histamine H1 receptor. Ser3.36 acts as a rotamer toggle switch that upon agonist binding initiates receptor activation through Asn7.45, involving conformational changes in helices 6 and 7. |
Site-directed mutagenesis, molecular modeling |
Nature chemical biology |
High |
16408006
|
| 2011 |
Crystal structure of the human histamine H1 receptor in complex with the first-generation antagonist doxepin was determined. Doxepin sits deep in the ligand-binding pocket and directly interacts with Trp428(6.48), a key residue in GPCR activation. The pocket has mostly hydrophobic character explaining low selectivity of first-generation compounds. Second-generation antagonists interact with Lys191(5.39) and/or Lys179(ECL2) in an anion-binding region not conserved in other aminergic receptors, explaining their selectivity. |
X-ray crystallography, molecular docking |
Nature |
High |
21697825
|
| 2005 |
HRH1 (histamine H1 receptor) activation in MA-10 murine and purified rat Leydig cells mediates inhibition of steroid synthesis. HRH1 activation increases inositol phosphate production, consistent with coupling to Gq protein and phospholipase C, while HRH2 activation stimulates steroidogenesis via adenylate cyclase/Gs. Selective agonists and antagonists confirmed these distinct receptor-pathway couplings. |
Pharmacological assay with selective agonists/antagonists, inositol phosphate assay, cAMP assay in Leydig cells |
Biology of reproduction |
Medium |
15917347
|
| 2016 |
HRH1-mediated sensitization of TRPV1 is involved in visceral hypersensitivity in irritable bowel syndrome. Supernatants from IBS rectal biopsies sensitized TRPV1 in mouse dorsal root ganglion neurons via HRH1; histamine and imidazole acetaldehyde reproduced this effect. Pyrilamine (HRH1 antagonist) blocked histamine-induced TRPV1 sensitization. The HRH1 antagonist ebastine reduced visceral hypersensitivity in a randomized placebo-controlled clinical trial. |
Live calcium imaging of submucosal neurons, mouse DRG neuron sensitization assay, pharmacological blockade, randomized controlled trial |
Gastroenterology |
High |
26752109
|
| 2021 |
Cryo-EM structure of the human histamine H1 receptor in complex with Gq protein in active conformation was determined. Histamine activates the receptor by interacting with key residues in TM3 and TM6, squashing the binding pocket on the extracellular side and opening a cavity on the intracellular side for Gq engagement. ICL2 of H1R interacts with the αN-β junction of Gq/11 protein. |
Cryo-electron microscopy, NanoBiT tethering strategy |
Nature communications |
High |
33828102
|
| 2018 |
Wild-type HRH1 synthesized in a wheat germ cell-free system with glycerosomes exhibited saturable binding to [3H]pyrilamine (Kd = 9.76 nM). A D107A mutant HRH1 (Asp107 replaced by Ala) showed markedly reduced and non-saturable binding to the H1 antagonist, confirming that Asp107 is critical for ligand binding. |
Cell-free protein synthesis, radioligand binding assay, mutant receptor analysis |
Frontiers in pharmacology |
Medium |
29467651
|
| 2025 |
HRH1 activates both Gαq and Gαi heterotrimers as shown by mini G protein recruitment and Gα activation assays in MDA-MB-231 cells. Pertussis toxin (PTx) disrupts histamine-induced Gαi binding to HRH1, causing a compensatory increase in Gαq binding and enhanced calcium signaling, which enables sensitive detection of PTx activity. |
Mini G protein recruitment assay, Gα activation assay, calcium signaling assay |
Vaccine |
Medium |
40158234
|
| 2017 |
Systematic membrane yeast two-hybrid (MYTH) mapping identified protein-protein interaction partners for human HRH1 among 686 proteins connected through 987 unique interactions across 48 GPCRs, providing a resource for HRH1 signaling pathway analysis. |
Membrane yeast two-hybrid (MYTH) interactome mapping |
Molecular systems biology |
Low |
28298427
|
| 2025 |
In glioblastoma, genetic silencing of HRH1 inhibited GBM cell proliferation, migration, and invasion in vitro and in vivo. The HRH1-targeting monoclonal antibody and the specific antagonist terfenadine exerted anti-tumor effects mechanistically through PKC-dependent regulation of the RAF/MEK/ERK signaling pathway. |
siRNA/shRNA knockdown, xenograft model, pharmacological antagonism with terfenadine, signaling pathway analysis |
Oncogene |
Medium |
41125791
|
| 2024 |
MSR1 overexpression in microglia increases phosphorylation of Akt via HRH1, expediting clearance of myelin debris through the PI3K/AKT pathway in ischemic white matter injury. MSR1-deficient mice showed exacerbated behavioral deficits and white matter injury after ischemic stroke. |
Gene knockout mouse model, overexpression studies, ischemic stroke model, pathway analysis |
Neuroscience letters |
Medium |
39214333
|
| 2025 |
Histamine promotes γδT17 cell differentiation through HRH1 in an Hrh1 receptor-dependent manner, with associated Wnt signaling pathway activation. RNA sequencing showed histamine exposure upregulated Hrh1 and activated the Wnt pathway, and in vitro experiments confirmed HRH1 dependence of this process. |
RNA sequencing, in vitro cell differentiation assay, pharmacological receptor blockade, pathway analysis |
International immunopharmacology |
Medium |
41014774
|
| 2003 |
Bphs/Hrh1 (histamine H1 receptor) controls susceptibility to pertussis toxin-induced histamine hypersensitivity and enhancement of antigen-specific delayed-type hypersensitivity responses. Using Bphs congenic and Hrh1 gene-disrupted mice, Hrh1 was shown to specifically mediate vasoactive amine sensitization to histamine but not serotonin, and did not influence lethal effects, leukocytosis, glucose regulation, or histamine-independent vascular permeability changes. |
Congenic mouse model, Hrh1 knockout mice, in vivo pertussis toxin challenge |
Infection and immunity |
Medium |
12595443
|
| 2023 |
In zebrafish, CRISPR/Cas9-generated hrh1-/- larvae showed transiently reduced tyrosine hydroxylase 1 (Th1)-positive (dopaminergic) cells and hypocretin-positive cells during early development, indicating HRH1 regulates dopaminergic and hypocretin/orexin systems. Adult hrh1-/- fish displayed impaired sociability and anxious-like behavior with downregulation of choline O-acetyltransferase a and LIM homeodomain transcription factor Islet1, suggesting HRH1 involvement in cholinergic and developmental gene regulation. |
CRISPR/Cas9 knockout, qPCR, in situ hybridization, immunocytochemistry, behavioral assays |
Molecular neurobiology |
Medium |
37474883
|
| 2025 |
MRGPRX2 activation on mast cells by HBD-2 (secreted from endometriotic cells) triggers histamine release, which sensitizes dorsal root ganglion sensory neurons via HRH1/TRPV1 signaling to produce endometriosis pain. Desloratadine (HRH1 antagonist) reversed histamine-induced Ca2+ influx in DRG cells. Mrgprb2-deficient mice showed reduced hyperalgesia and lesion size. |
In vitro mast cell culture, Ca2+ imaging in DRG neurons, pharmacological antagonism, Mrgprb2 KO mouse model |
FASEB journal |
Medium |
40600649
|
| 2025 |
Phenotypic screening and SCOPE computational enrichment identified HRH1 as a regulator of ER stress-induced exodosis (secretion of ER-resident proteins). This was validated by RNAi knockdown and pharmacological inhibition of HRH1, implicating HRH1-mediated calcium signaling (via Gq/IP3R pathway) in regulation of exodosis. |
High-throughput phenotypic screen, SCOPE pathway enrichment, RNAi knockdown, pharmacological inhibition |
bioRxivpreprint |
Low |
|
| 2025 |
In cutaneous squamous cell carcinoma with perineural invasion, tumor cells express elevated HRH1, and histamine from mast cells enhances tumor invasion into nerves via broad upregulation of matrix metalloproteinases (MMPs) through P38 activation, enabling collagen degradation in the nerve sheath. H1-antihistamines rescued this effect in PNI organoid models. |
Single-cell transcriptomics, PNI organoid model, pharmacological H1 blockade, MMP/P38 pathway analysis |
bioRxivpreprint |
Low |
|