HRH2 encodes the histamine H2 receptor, a class A seven-transmembrane G-protein-coupled receptor of the plasma membrane. Histamine binding in its transmembrane pocket couples the receptor to Gs, activating adenylate cyclase and raising cAMP. It is best known for driving gastric parietal cell acid secretion, and is also expressed in the heart, immune cells (where it shifts cytokine output toward IL-10 over IL-12) and the central nervous system, where it mediates histaminergic neurotransmission.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001696 gastric acid secretion | IEA GO_REF:0000002 | ACCEPT | Summary: HRH2 mediates gastric acid secretion. Reason: Its principal physiological role; H2 activation stimulates parietal cells to secrete hydrochloric acid. Supporting Evidence: file:human/HRH2/HRH2-uniprot.txt stimulates parietal cells to secrete hydrochloric acid |
| GO:0004930 G protein-coupled receptor activity | IEA GO_REF:0000002 | MODIFY | Summary: Generic GPCR activity from the 7TM InterPro mapping. Reason: Correct but general; HRH2's specific activity is histamine receptor activity, already asserted experimentally. Proposed replacements: histamine receptor activity Supporting Evidence: file:human/HRH2/HRH2-uniprot.txt G protein-coupled receptor for histamine |
| GO:0004969 histamine receptor activity | IBA GO_REF:0000033 | ACCEPT | Summary: HRH2 is the H2 receptor for histamine. Reason: Its defining molecular function, supported by IDA, IBA and the receptor-cloning study. Supporting Evidence: file:human/HRH2/HRH2-uniprot.txt G protein-coupled receptor for histamine PMID:39462031 via the HRH2 histamine receptor |
| GO:0004969 histamine receptor activity | IDA PMID:39462031 Histamine stimulates human microglia to alter cellular prion... | ACCEPT | Summary: HRH2 is the H2 receptor for histamine. Reason: Its defining molecular function, supported by IDA, IBA and the receptor-cloning study. Supporting Evidence: file:human/HRH2/HRH2-uniprot.txt G protein-coupled receptor for histamine PMID:39462031 via the HRH2 histamine receptor |
| GO:0004969 histamine receptor activity | IEA GO_REF:0000002 | ACCEPT | Summary: HRH2 is the H2 receptor for histamine. Reason: Its defining molecular function, supported by IDA, IBA and the receptor-cloning study. Supporting Evidence: file:human/HRH2/HRH2-uniprot.txt G protein-coupled receptor for histamine PMID:39462031 via the HRH2 histamine receptor |
| GO:0004969 histamine receptor activity | TAS PMID:9725260 Histamine potently suppresses human IL-12 and stimulates IL-... | ACCEPT | Summary: HRH2 is the H2 receptor for histamine. Reason: Its defining molecular function, supported by IDA, IBA and the receptor-cloning study. Supporting Evidence: file:human/HRH2/HRH2-uniprot.txt G protein-coupled receptor for histamine PMID:39462031 via the HRH2 histamine receptor |
| GO:0005515 protein binding | IPI PMID:39083597 Multiplexed mapping of the interactome of GPCRs with recepto... | REMOVE | Summary: Protein binding to RAMP2/RAMP3 from a GPCR-RAMP interactome screen. Reason: Bare protein binding is uninformative and removed under the protein-binding policy. The interaction is with receptor activity-modifying proteins (RAMP2/RAMP3) but no specific RAMP-binding molecular-function term exists; removal does not dispute the interaction. Supporting Evidence: PMID:39083597 Multiplexed mapping of the interactome of GPCRs with receptor activity-modifying |
| GO:0005515 protein binding | IPI PMID:39083597 Multiplexed mapping of the interactome of GPCRs with recepto... | REMOVE | Summary: Protein binding to RAMP2/RAMP3 from a GPCR-RAMP interactome screen. Reason: Bare protein binding is uninformative and removed under the protein-binding policy. The interaction is with receptor activity-modifying proteins (RAMP2/RAMP3) but no specific RAMP-binding molecular-function term exists; removal does not dispute the interaction. Supporting Evidence: PMID:39083597 Multiplexed mapping of the interactome of GPCRs with receptor activity-modifying |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: HRH2 is a cell-surface plasma-membrane GPCR. Reason: As a multi-pass GPCR it resides in the plasma membrane with its ligand-binding pocket accessible from the extracellular side; supported by IBA, Reactome and subcellular mapping. Supporting Evidence: file:human/HRH2/HRH2-uniprot.txt Cell membrane; Multi-pass membrane protein |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: HRH2 is a cell-surface plasma-membrane GPCR. Reason: As a multi-pass GPCR it resides in the plasma membrane with its ligand-binding pocket accessible from the extracellular side; supported by IBA, Reactome and subcellular mapping. Supporting Evidence: file:human/HRH2/HRH2-uniprot.txt Cell membrane; Multi-pass membrane protein |
| GO:0005886 plasma membrane | TAS PMID:1714721 Molecular cloning of the human histamine H2 receptor. | ACCEPT | Summary: HRH2 is a cell-surface plasma-membrane GPCR. Reason: As a multi-pass GPCR it resides in the plasma membrane with its ligand-binding pocket accessible from the extracellular side; supported by IBA, Reactome and subcellular mapping. Supporting Evidence: file:human/HRH2/HRH2-uniprot.txt Cell membrane; Multi-pass membrane protein |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-379044 | ACCEPT | Summary: HRH2 is a cell-surface plasma-membrane GPCR. Reason: As a multi-pass GPCR it resides in the plasma membrane with its ligand-binding pocket accessible from the extracellular side; supported by IBA, Reactome and subcellular mapping. Supporting Evidence: file:human/HRH2/HRH2-uniprot.txt Cell membrane; Multi-pass membrane protein |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-390909 | ACCEPT | Summary: HRH2 is a cell-surface plasma-membrane GPCR. Reason: As a multi-pass GPCR it resides in the plasma membrane with its ligand-binding pocket accessible from the extracellular side; supported by IBA, Reactome and subcellular mapping. Supporting Evidence: file:human/HRH2/HRH2-uniprot.txt Cell membrane; Multi-pass membrane protein |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-744886 | ACCEPT | Summary: HRH2 is a cell-surface plasma-membrane GPCR. Reason: As a multi-pass GPCR it resides in the plasma membrane with its ligand-binding pocket accessible from the extracellular side; supported by IBA, Reactome and subcellular mapping. Supporting Evidence: file:human/HRH2/HRH2-uniprot.txt Cell membrane; Multi-pass membrane protein |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-744887 | ACCEPT | Summary: HRH2 is a cell-surface plasma-membrane GPCR. Reason: As a multi-pass GPCR it resides in the plasma membrane with its ligand-binding pocket accessible from the extracellular side; supported by IBA, Reactome and subcellular mapping. Supporting Evidence: file:human/HRH2/HRH2-uniprot.txt Cell membrane; Multi-pass membrane protein |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9692738 | ACCEPT | Summary: HRH2 is a cell-surface plasma-membrane GPCR. Reason: As a multi-pass GPCR it resides in the plasma membrane with its ligand-binding pocket accessible from the extracellular side; supported by IBA, Reactome and subcellular mapping. Supporting Evidence: file:human/HRH2/HRH2-uniprot.txt Cell membrane; Multi-pass membrane protein |
| GO:0006955 immune response | TAS PMID:9725260 Histamine potently suppresses human IL-12 and stimulates IL-... | KEEP AS NON CORE | Summary: Immune response modulation via H2. Reason: H2 signaling suppresses IL-12 and stimulates IL-10 in human monocytes; a genuine but non-core immunomodulatory role. Supporting Evidence: PMID:9725260 Histamine potently suppresses human IL-12 and stimulates IL-10 production via H2 receptors |
| GO:0007186 G protein-coupled receptor signaling pathway | IEA GO_REF:0000002 | MODIFY | Summary: Generic GPCR signaling pathway. Reason: Correct but general; HRH2 signals specifically through the adenylate cyclase-activating GPCR pathway, a descendant term already asserted for this gene. Proposed replacements: adenylate cyclase-activating G protein-coupled receptor signaling pathway Supporting Evidence: file:human/HRH2/HRH2-uniprot.txt activation of adenylate cyclase |
| GO:0007187 G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: GPCR signaling coupled to a cyclic nucleotide (cAMP) second messenger. Reason: HRH2 signaling raises cAMP, so this term is accurate; it sits in a parallel second- messenger branch rather than being entailed by the adenylate-cyclase-activating term, and is retained as a non-core description of the same signaling output. Supporting Evidence: file:human/HRH2/HRH2-uniprot.txt increased intracellular cyclic |
| GO:0007187 G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger | TAS PMID:9725260 Histamine potently suppresses human IL-12 and stimulates IL-... | KEEP AS NON CORE | Summary: GPCR signaling coupled to a cyclic nucleotide (cAMP) second messenger. Reason: HRH2 signaling raises cAMP, so this term is accurate; it sits in a parallel second- messenger branch rather than being entailed by the adenylate-cyclase-activating term, and is retained as a non-core description of the same signaling output. Supporting Evidence: file:human/HRH2/HRH2-uniprot.txt increased intracellular cyclic |
| GO:0007189 adenylate cyclase-activating G protein-coupled receptor signaling pathway | TAS PMID:9725260 Histamine potently suppresses human IL-12 and stimulates IL-... | ACCEPT | Summary: HRH2 activates adenylate cyclase via Gs. Reason: The defining signaling output; histamine-bound HRH2 couples to Gs and activates adenylate cyclase to raise cAMP. Supporting Evidence: file:human/HRH2/HRH2-uniprot.txt couples to G(s) G alpha proteins upon histamine binding, leading to activation of adenylate cyclase |
| GO:0007268 chemical synaptic transmission | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Chemical synaptic transmission (histaminergic neurotransmission). Reason: HRH2 participates in CNS histaminergic transmission; a non-core process. Supporting Evidence: file:human/HRH2/HRH2-uniprot.txt modulate neurotransmitter release |
| GO:0016020 membrane | IEA GO_REF:0000002 | TOO GENERAL | Summary: Membrane, generic parent of the asserted plasma membrane localization. Reason: HRH2 is specifically a plasma-membrane protein (asserted); the bare membrane term is entailed by it. Supporting Evidence: file:human/HRH2/HRH2-uniprot.txt Cell membrane; Multi-pass membrane protein |
| GO:0030425 dendrite | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Dendritic localization in neurons. Reason: Consistent with CNS histaminergic signaling; a non-core neuronal location. Supporting Evidence: file:human/HRH2/HRH2-uniprot.txt central nervous system |
| GO:0030594 neurotransmitter receptor activity | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Histamine neurotransmitter receptor activity in the CNS. Reason: In the brain HRH2 acts as a histaminergic neurotransmitter receptor; a genuine but non-core activity relative to its gastric role. Supporting Evidence: file:human/HRH2/HRH2-uniprot.txt modulate neurotransmitter release |
| GO:0045202 synapse | IEA GO_REF:0000108 | KEEP AS NON CORE | Summary: Synapse localization (inferred from synaptic transmission). Reason: Reflects HRH2's neuronal/synaptic role; non-core relative to its gastric function. Supporting Evidence: file:human/HRH2/HRH2-uniprot.txt central nervous system |
| GO:0045907 positive regulation of vasoconstriction | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: Positive regulation of vasoconstriction, from an InterPro2GO domain mapping. Reason: This IEA derives from a generic histamine-receptor domain mapping. H2-receptor vascular effects are predominantly vasodilatory (cAMP-mediated relaxation), so attributing positive regulation of vasoconstriction to HRH2 over-annotates the protein. Supporting Evidence: file:human/HRH2/HRH2-uniprot.txt activation of adenylate cyclase |
Loading supporting content…
Download this section (compressed HTML)Q: Do RAMP2/RAMP3 interactions alter HRH2 trafficking, ligand pharmacology or G-protein coupling in vivo?
Q: How do tissue-specific HRH2 expression and desensitization explain tolerance to H2 antihistamines used for acid suppression?
Experiment: Cryo-EM of the histamine-HRH2-Gs complex to define the agonist-binding pocket and the basis of H2 selectivity.
Type: structural biology
Experiment: Reconstitute HRH2 with and without RAMP2/RAMP3 and measure cAMP responses and surface expression to test RAMP modulation.
Type: pharmacology
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)