Affinage

Showing HCRTR1 — OX1R is a alias.

HCRTR1

Orexin/Hypocretin receptor type 1 · UniProt O43613

Length
425 aa
Mass
47.5 kDa
Annotated
2026-06-10
56 papers in source corpus 23 papers cited in narrative 23 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HCRTR1 (OX1R) is a Gq-coupled G protein-coupled receptor for orexin-A that transduces ligand binding into divergent signaling outputs controlling neuronal excitability, cell survival, autophagy, and behavior (PMID:18198212, PMID:33515654). Canonical Gq signaling drives an IP3/intracellular Ca2+/PKC cascade that modulates ion channels in spinal ventral horn neurons, potentiating glycine currents (PMID:33515654) and, together with OX2R via a Ca2+-independent PKC route, suppressing GABA currents (PMID:34134956). In parallel, OX1R executes a non-canonical, phospholipase C-independent death pathway: freed Gq βγ activates Src, which phosphorylates an ITIM at Y358 and an ITSM at Y83 in the receptor's intracellular regions, recruiting SHP-2 to trigger cytochrome c release and caspase-3/7 activation in cancer cells (PMID:18198212, PMID:19661287, PMID:21627633). Beyond these, OX1R engages PI3K/AKT, MAPK/ERK, and mTOR/p70S6K1 cascades to control cell survival, autophagy, and steroidogenesis—protecting hepatocytes and neurons from apoptosis (PMID:24807827, PMID:33212156), suppressing autophagy to promote cortisol secretion in adrenocortical cells (PMID:37572990), and limiting inflammatory NF-κB signaling (PMID:34358627, PMID:30251681). OX1R forms constitutive heterodimers with GHSR1a and APJ that reshape its G protein coupling and trafficking (PMID:30065627, PMID:31668922). In the CNS, OX1R signaling in defined nuclei contributes to behavioral despair (PMID:21377495), VTA dopamine neuron excitability and associated anxiety/addiction phenotypes [PMID:bio_10.1101_2025.02.14.638329, PMID:bio_10.1101_2024.09.07.609774], and cardiorespiratory regulation (PMID:19995618, PMID:41369031). α-Synuclein binds OX1R directly and promotes its proteasomal and lysosomal degradation, linking receptor turnover to orexin neuron dysfunction (PMID:36689149).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2008 High

    Established that OX1R signals to apoptosis through a previously unrecognized tyrosine-based motif rather than its canonical Ca2+ pathway, redefining the receptor as a death-signaling GPCR in cancer.

    Evidence Y358F mutagenesis, transfection in CHO cells, Gαq-null fibroblasts, PLC inhibitor, dominant-negative SHP-2

    PMID:18198212

    Open questions at the time
    • Did not identify the upstream tyrosine kinase phosphorylating Y358
    • Generality across non-cancer cell types untested
  2. 2009 High

    Showed that a second motif (ITSM Y83) is co-required with the ITIM, defining a bipartite phosphotyrosine docking site for both SHP-2 SH2 domains and clarifying how the receptor engages the phosphatase.

    Evidence Y83F mutagenesis, IP/calcium and SHP-2 recruitment assays, computational structural modeling

    PMID:19661287

    Open questions at the time
    • Structural model not experimentally validated
    • Stoichiometry of OX1R-SHP-2 binding not directly measured
  3. 2012 Medium

    Consolidated the death pathway by identifying Gq βγ-activated Src as the kinase upstream of ITIM phosphorylation in colon cancer, completing a receptor-to-mitochondria signaling chain.

    Evidence Review synthesizing Gq-null cell, PLC inhibitor, dominant-negative SHP-2 and caspase data

    PMID:21627633

    Open questions at the time
    • Single-group synthesis without independent replication
    • Direct demonstration that βγ-Src acts on OX1R in situ limited
  4. 2014 Medium

    Demonstrated that OX1R can also be pro-survival via PI3K/AKT-FoxO1-mTORC1, establishing context-dependence of orexin signaling outcomes.

    Evidence Pharmacological inhibitors at multiple pathway nodes in primary rat hepatocytes

    PMID:24807827

    Open questions at the time
    • Did not reconcile pro-survival vs pro-apoptotic outcomes mechanistically
    • Single tissue context
  5. 2015 Low

    Provided a structural hypothesis for orexin-A engagement of OX1R, proposing alternative binding modes consistent with mutagenesis.

    Evidence Homology modeling on OX2R/NTSR1/CXCR4 templates with docking and clustering

    PMID:25957175

    Open questions at the time
    • Computational only; no experimental validation of binding modes
    • Cannot distinguish which mode is functional
  6. 2018 Medium

    Showed that OX1R does not signal in isolation but forms a constitutive heterodimer with GHSR1a that reprograms G protein coupling toward Gs/cAMP, expanding the receptor's signaling repertoire.

    Evidence BRET, FRET, Co-IP, TM5 peptide interference, cAMP and CRE-luciferase assays

    PMID:30065627

    Open questions at the time
    • In vivo relevance of heterodimer not established
    • Single lab
  7. 2019 Medium

    Extended heterodimerization to APJ, defining the TM4/TM5 interface and showing co-internalization, indicating combinatorial regulation of OX1R trafficking.

    Evidence BRET, reciprocal Co-IP, immunostaining, TM peptide interference

    PMID:31668922

    Open questions at the time
    • Functional signaling consequences of APJ-OX1R heterodimer not quantified
    • Single lab
  8. 2021 High

    Dissected the canonical OX1R cascade in native spinal neurons, showing IP3/intracellular Ca2+/PKC potentiates glycine currents while a Ca2+-independent PKC route (OX1R+OX2R) inhibits GABA currents, mapping receptor coupling to specific inhibitory neurotransmission.

    Evidence Patch-clamp with subtype-selective antagonists, Ca2+ chelation, IP3R and PKC inhibitors/activators

    PMID:33515654 PMID:34134956

    Open questions at the time
    • Target ion channels not molecularly identified
    • PKC isoform specificity not resolved
  9. 2021 Medium

    Established OX1R as a neuroprotective/anti-inflammatory node in cerebral ischemia via MAPK/ERK/mTOR control of autophagy and NF-κB/MAPK suppression, broadening its physiological roles.

    Evidence Western blot, viability/apoptosis assays in MCAO/R rat and OGD/R cell models with OX1R antagonism

    PMID:33212156 PMID:34358627

    Open questions at the time
    • Receptor assignment based largely on pathway readouts and antagonist
    • No genetic loss-of-function in these models
  10. 2023 Medium

    Identified α-synuclein as a direct binding partner that drives OX1R degradation through proteasomal and lysosomal routes, linking receptor turnover to orexin neuron loss and sleep pathology.

    Evidence Co-IP, proteasome/lysosome inhibitors, lentiviral overexpression, in vivo LHA injection, sleep analysis

    PMID:36689149

    Open questions at the time
    • Binding interface on OX1R not mapped
    • E3 ligase mediating degradation unknown
  11. 2023 Medium

    Connected OX1R-mTOR/p70S6K1 autophagy suppression to steroidogenesis, showing the receptor regulates cortisol output via 3β-HSD induction.

    Evidence TEM, western blot, ELISA with OX1R and mTOR inhibitors in adrenocortical lines

    PMID:37572990

    Open questions at the time
    • Causal link between autophagy and 3β-HSD not fully isolated
    • Single lab
  12. 2024 Medium

    Used cell-type-specific deletion to place OX1R signaling in CRF neurons upstream of excessive alcohol consumption and BNST excitability, establishing circuit-level behavioral causality.

    Evidence Conditional HcrtR1 KO in CRF neurons, drinking assays, BNST patch-clamp (preprint)

    PMID:bio_10.1101_2024.09.07.609774

    Open questions at the time
    • Preprint, single lab
    • Sex-specific mechanism not resolved
  13. 2025 Medium

    Demonstrated that OX1R mediates orexin-A excitation of VTA dopamine neurons and is required for normal anxiety and activity behaviors, anchoring the receptor in dopaminergic circuit function.

    Evidence DA-cell-specific Hcrtr1 KO, VTA patch-clamp, behavioral phenotyping; LH ox/dyn optogenetics (preprints)

    PMID:bio_10.1101_2024.08.01.606179 PMID:bio_10.1101_2025.02.14.638329

    Open questions at the time
    • Preprints, single lab
    • Downstream effectors of DA neuron excitation not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How OX1R selects between pro-apoptotic (Src/SHP-2), pro-survival (PI3K/AKT), and canonical Ca2+/PKC outputs in a cell-context-dependent manner remains unresolved.
  • No unifying model linking ligand/cofactor context to pathway choice
  • Heterodimer contribution to output selection in vivo unknown
  • No experimental high-resolution structure of OX1R complexes in the corpus

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0001618 virus receptor activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-9612973 Autophagy 2
Partners
APJGHSR1ASHP-2SNCASRC
Complex memberships
APJ-OX1R heterodimerGHSR1a-OX1R heterodimer

Evidence

Reading pass · 23 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 OX1R contains an immunoreceptor tyrosine-based inhibitory motif (ITIM) at Y358 that drives apoptosis in cancer cells. Orexin-induced apoptosis requires Gq protein coupling but is independent of phospholipase C activation; instead, Y358 phosphorylation recruits SHP-2 phosphatase. Mutation of Y358 to F abolished ITIM tyrosine phosphorylation, SHP-2 recruitment, and apoptosis, but not inositol phosphate formation or calcium signaling. Site-directed mutagenesis (Y358F), transfection in CHO cells, tyrosine phosphatase inhibitor (PAO), dominant-negative SHP-2, Gαq-null fibroblasts, phospholipase C inhibitor U-73122 FASEB journal High 18198212
2009 OX1R also contains a functional immunoreceptor tyrosine-based switch motif (ITSM) at Y83 in the first intracellular loop that is mandatory for OX1R-mediated apoptosis. Mutation of Y83 to F abolished ITSM phosphorylation, SHP-2 recruitment, and apoptosis, without altering Gq-mediated inositol phosphate formation or calcium transients. A structural model showed ITSM and ITIM phosphotyrosines are spatially compatible with simultaneous interaction with both SH2 domains of SHP-2. Site-directed mutagenesis (Y83F), functional IP/calcium assays, SHP-2 recruitment assays, computational structural modeling of OX1R FASEB journal High 19661287
2012 OX1R drives apoptosis in colon cancer cells through a Gq protein-dependent but phospholipase C-independent mechanism: the freed Gq βγ dimer stimulates Src-tyrosine kinase, which phosphorylates the ITIM motifs in OX1R, leading to SHP-2 recruitment and activation, followed by cytochrome c release and caspase-3/7 activation. Review consolidating prior experimental data; downstream pathway shown by pharmacological and genetic perturbations in prior studies (Gq null cells, PLC inhibitors, SHP-2 dominant-negative, caspase assays) British journal of pharmacology Medium 21627633
2018 GHSR1a (ghrelin receptor) and OX1R form constitutive heterodimers, demonstrated by BRET, FRET, and co-immunoprecipitation. A peptide mimicking the 5th transmembrane domain of OX1R impaired heterodimer formation. In GHSR1a/OX1R heterodimer-expressing cells, ghrelin (but not orexin-A) shifted signaling from Gαq to Gαs, increasing cAMP and CREB reporter activity compared to GHSR1a alone. BRET, FRET, Co-IP, transmembrane peptide interference, cAMP assay, CRE-luciferase reporter Frontiers in molecular neuroscience Medium 30065627
2019 APJ (apelin receptor) and OX1R form a constitutive GPCR heterodimer. Both receptors co-internalize upon stimulation with their respective agonists (apelin-13 or orexin-A). In vitro transmembrane peptide interference experiments using BRET and immunostaining identified TM4 and TM5 of APJ as the interaction interface of the APJ-OX1R heterodimer; co-internalization was disrupted by these peptides. BRET, Co-IP, immunostaining, transmembrane peptide interference assays Biochemical and biophysical research communications Medium 31668922
2015 Computational modeling of OX1R using the OX2R crystal structure as template revealed two alternative binding modes for orexin-A peptide (C-terminus in binding pocket near Tyr6.48 and Gln3.32), differing by ~100° peptide rotation, both consistent with prior site-directed mutagenesis data. Homology modeling (based on OX2R, NTSR1, CXCR4 structures), ZDOCK/RDOCK docking of 4301 complexes, multidimensional scaling and clustering BMC structural biology Low 25957175
2014 Orexin-A protects rat hepatocytes from apoptosis via the OX1R/PI3K/AKT signaling pathway, inducing phosphorylation of FoxO1 and mTORC1. OX1R antagonist SB334867, AKT antagonist, FoxO1 inhibitor, and mTORC1 inhibitor each blocked these effects. RT-PCR, western blot, pharmacological inhibitors (SB334867, PF-04691502, AS1842856, everolimus), cell viability and apoptosis assays in primary rat hepatocytes International journal of molecular medicine Medium 24807827
2016 Orexin-A promotes glutamate (Glu) uptake in astrocytes under anoxia/hypoglycemic conditions via OX1R, upregulating GLT-1 expression through a PKCα/ERK1/2 signaling cascade. OX1R antagonist reversed these effects; PKCα or ERK1/2 inhibitors constrained GLT-1 expression; GLT-1 overexpression rescued cells from the inhibitor-induced apoptosis. Pharmacological inhibitors (OX1R antagonist, PKCα inhibitor, ERK1/2 inhibitor), GLT-1 overexpression, western blot, Glu uptake assay in astrocytes under OGD conditions Molecular and cellular biochemistry Medium 27837432
2020 Orexin-A exerts neuroprotective effects in cerebral ischemia-reperfusion injury by suppressing over-activated autophagy through the OX1R-mediated MAPK/ERK/mTOR pathway, reducing neuronal apoptosis. OX1R was identified as the mediating receptor based on pathway protein levels (p-ERK1/2, p-mTOR, LC3B, Beclin-1, p62) in MCAO rats and OGD/R cells. Western blot, CCK8 cell viability, acridine orange staining (autophagic vacuoles), Hoechst/TUNEL apoptosis assays, MCAO rat model and OGD/R cell model Cellular signalling Medium 33212156
2021 Orexin-A alleviates astrocytic apoptosis and inflammation in cerebral ischemia/reperfusion injury by inhibiting OX1R-mediated NF-κB and MAPK/ERK and MAPK/p38 signaling pathways, including suppression of nuclear translocation of NF-κB p65 and upregulation of Bcl-2/Bax ratio. Western blot, ELISA, Hoechst staining, immunofluorescence, TTC staining, MCAO/R rat model and OGD/R U251 cell model Biochimica et biophysica acta. Molecular basis of disease Medium 34358627
2021 Orexin-A potentiates glycine currents in spinal cord ventral horn neurons by activating OX1R via an IP3/intracellular Ca2+/PKC-dependent signaling pathway. Extracellular Ca2+ removal did not block the effect; chelation of intracellular Ca2+ with BAPTA or blockade of IP3 receptors (heparin, Xe-C) abolished it; PKC inhibitor (Bis-IV) nullified the effect; PKC activator (PMA) occluded the orexin-A effect. Patch-clamp electrophysiology in acutely isolated spinal neurons, OX1R antagonist (SB334867), Ca2+-free solution, BAPTA internal infusion, IP3 receptor antagonists, PKC inhibitor/activator Brain research bulletin High 33515654
2021 Orexin-A inhibits GABA currents in spinal cord ventral horn neurons by activating both OX1R and OX2R via a Ca2+-independent PKC signaling pathway. Simultaneous blockade of OX1R and OX2R completely abolished the suppressive effect; separate blockade partially relieved it. PKC inhibitor (Bis-IV) abolished the effect; PKC activator (PMA) occluded it; Rp-cAMP (PKA inhibitor) did not affect it; Ca2+ chelation did not significantly change the effect. Patch-clamp electrophysiology, selective OX1R antagonist (SB334867) and OX2R antagonist (TCSOX229), PKC inhibitor/activator, PKA inhibitor, Ca2+ chelator BAPTA, Ca2+-free extracellular solution Journal of Southern Medical University High 34134956
2018 Orexin-A exerts neuroprotective effects on MPTP-treated parkinsonian mice via OX1R, increasing BDNF protein in dopaminergic neurons. The protective effects were blocked by OX1R antagonist SB334867. In SH-SY5Y cells, orexin-A induced BDNF upregulation via OX1R through PI3K and PKC signaling pathways. MPTP mouse model of PD, OX1R antagonist (SB334867), Western blot, immunohistochemistry, behavioral assays, pharmacological inhibitors of PI3K and PKC in SH-SY5Y cells Frontiers in neuroscience Medium 30524223
2023 α-Synuclein physically interacts with OX1R and promotes OX1R degradation through both proteasomal and lysosomal pathways. Overexpression of α-Synuclein downregulated OX1R-mediated signaling and damaged orexin neurons. In vivo injection of α-Synuclein into the lateral hypothalamic area damaged orexin neurons and induced RBD-like sleep patterns. Co-immunoprecipitation (interaction), proteasome/lysosome inhibitor experiments (degradation pathway), lentiviral overexpression, in vivo stereotaxic injection, sleep pattern analysis, western blot Neuromolecular medicine Medium 36689149
2023 Orexin-A/OX1R activates the mTOR/p70S6K1 pathway to inhibit autophagy in adrenocortical cells (H295R and Y-1), and this autophagy suppression promotes cortisol secretion by increasing expression of 3β-hydroxysteroid dehydrogenase/isomerase. Transmission electron microscopy (autophagosomes), western blot (LC3, p62, mTOR, p70S6K1), ELISA (cortisol), OX1R antagonist and mTOR inhibitor treatments in adrenocortical cell lines Biochimica et biophysica acta. Molecular basis of disease Medium 37572990
2021 Cannabidiol (CBD) acts as a selective antagonist at OX1R (Ki ~1.58 μM) with no significant binding at OX2R. In vitro functional assays (intracellular calcium imaging and mobilization) confirmed CBD antagonism at OX1R. Molecular docking rationalized the OX1R subtype selectivity at the molecular level. Radioligand binding assay (Ki determination), intracellular calcium imaging, calcium mobilization assay, molecular docking and molecular dynamics Biomolecules Medium 34439801
2009 OX1R in the rostral medullary raphe contributes to the hypercapnic chemoreflex specifically during wakefulness in the dark (active) period in rats. Focal OX1R antagonism by microdialysis of SB-334867 into the rostral medullary raphe caused a 16% reduction in CO2-induced hyperventilation during wakefulness in the dark period, with no effect during NREM sleep or in the light period. Microdialysis of selective OX1R antagonist (SB-334867) into rostral medullary raphe, ventilation measurement in air and 7% CO2, state-dependent analysis (wakefulness vs. sleep, dark vs. light period) Respiratory physiology & neurobiology Medium 19995618
2011 Hcrtr1 signaling specifically promotes depression-like behavioral despair: Hcrtr1-null mice showed significantly reduced behavioral despair in forced swim and tail suspension tests, and wild-type mice treated with OX1R antagonist SB-334867 recapitulated this effect. No anxiety-like behavior difference was noted with hcrtr1 deletion, in contrast to hcrtr2-null mice which showed increased behavioral despair. Genetic knockout (Hcrtr1-null mice), pharmacological antagonism (SB-334867), forced swim test, tail suspension test, anxiety-like behavior assays Behavioural brain research Medium 21377495
2018 OX1R is ectopically expressed in ulcerative colitis-affected colonic epithelium and mediates the anti-inflammatory effect of orexin-A. Injection of orexin-A improved inflammatory symptoms in two colitis murine models, while an inactive orexin-A analog, OX1R-specific antagonist SB-408124, or treatment of OX1R knockout mice with orexin-A had no protective effect. Orexin-A decreased pro-inflammatory cytokines in immune cells, particularly T-cells, and inhibited canonical NF-κB activation. Immunohistochemistry (OX1R expression in UC), two colitis mouse models (DSS), OX1R knockout mice, OX1R antagonist (SB-408124), inactive analog control, cytokine assays, NF-κB activation assay Biochimica et biophysica acta. Molecular basis of disease Medium 30251681
2025 OX1R-specific loss in dopaminergic VTA neurons (DA-Ox1R-KO mice) abolished the excitatory response of DA VTA cells to OXA (orexin-A), demonstrating that OXA enhances DA VTA neuronal excitability specifically through OX1R. DA-Ox1R-KO mice displayed anxiety-like behavior and context-dependent hyperactivity, placing OX1R signaling in DA neurons upstream of these behavioral outputs. Conditional genetic knockout (Hcrtr1 selectively deleted in DA cells), patch-clamp electrophysiology of VTA DA neurons, behavioral phenotyping bioRxivpreprint Medium bio_10.1101_2025.02.14.638329
2024 Optical stimulation of lateral hypothalamic orexin/dynorphin (LH-ox/dyn) inputs in the VTA activates DA VTA neurons via Ox1R signaling. The diverse firing responses of VTA DA neurons to LH optical stimulation were blocked by Ox1R antagonism (alongside KOR blockade), and projection-specific effects were observed: LH ox/dyn input inhibited BLA-projecting DA neurons (dynorphin predominating via KOR) and bidirectionally modulated nucleus accumbens-projecting DA neurons sensitive to both Ox1R and KOR. Optogenetics, patch-clamp electrophysiology, circuit tracing, pharmacological blockade of Ox1R and KOR in orexin-Cre mice bioRxivpreprint Medium bio_10.1101_2024.08.01.606179
2025 OX1R in the paraventricular nucleus (PVN) contributes to SF-induced aggravation of myocardial ischemia-reperfusion injury via sympathetic hyperactivation. PVN OX1R expression was upregulated by sleep fragmentation. Pharmacological blockade of OX1R in the PVN with SB-334867 (stereotaxic injection) significantly ameliorated cardiac dysfunction, reduced infarct size, and suppressed sympathetic hyperactivity. Stereotaxic OX1R antagonist (SB-334867) injection into PVN, echocardiography, heart rate variability analysis, western blot, qRT-PCR, immunohistochemistry in SF mouse model Annals of medicine Medium 41369031
2024 CRF neuron-specific deletion of HcrtR1 (OX1R) significantly reduced alcohol intake in mice, with sex-specific effects on BNST excitability during protracted withdrawal. These genetic epistasis experiments place HcrtR1 signaling in CRF neurons upstream of excessive alcohol consumption behavior. Conditional genetic knockout (HcrtR1 deleted specifically in CRF neurons), alcohol drinking assays, patch-clamp electrophysiology (BNST excitability), anxiety behavioral tests, sex-specific analysis bioRxivpreprint Medium bio_10.1101_2024.09.07.609774

Source papers

Stage 0 corpus · 56 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Hcrtr1 and 2 signaling differentially regulates depression-like behaviors. Behavioural brain research 109 21377495
2021 Orexin-A alleviates astrocytic apoptosis and inflammation via inhibiting OX1R-mediated NF-κB and MAPK signaling pathways in cerebral ischemia/reperfusion injury. Biochimica et biophysica acta. Molecular basis of disease 102 34358627
2015 Comprehensive Behavioral Analysis of Male Ox1r (-/-) Mice Showed Implication of Orexin Receptor-1 in Mood, Anxiety, and Social Behavior. Frontiers in behavioral neuroscience 78 26696848
2009 The orexin receptor 1 (OX1R) in the rostral medullary raphe contributes to the hypercapnic chemoreflex in wakefulness, during the active period of the diurnal cycle. Respiratory physiology & neurobiology 56 19995618
2018 Orexin-A Exerts Neuroprotective Effects via OX1R in Parkinson's Disease. Frontiers in neuroscience 54 30524223
2020 Orexin-A protects against cerebral ischemia-reperfusion injury by inhibiting excessive autophagy through OX1R-mediated MAPK/ERK/mTOR pathway. Cellular signalling 53 33212156
2008 A hallmark of immunoreceptor, the tyrosine-based inhibitory motif ITIM, is present in the G protein-coupled receptor OX1R for orexins and drives apoptosis: a novel mechanism. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 51 18198212
2010 Expression of orexin receptors 1 (OX1R) and 2 (OX2R) in the porcine ovary during the oestrous cycle. Regulatory peptides 45 20688107
2009 Discovery of a functional immunoreceptor tyrosine-based switch motif in a 7-transmembrane-spanning receptor: role in the orexin receptor OX1R-driven apoptosis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 45 19661287
2015 Distribution of the orexin-1 receptor (OX1R) in the mouse forebrain and rostral brainstem: A characterisation of OX1R-eGFP mice. Journal of chemical neuroanatomy 44 25841630
2005 Effect of a selective OX1R antagonist on food intake and body weight in two strains of rats that differ in susceptibility to dietary-induced obesity. Peptides 41 15893404
2012 The differential effects of OX1R and OX2R selective antagonists on morphine conditioned place preference in naïve versus morphine-dependent mice. Behavioural brain research 38 22995645
2013 Kinetic properties of "dual" orexin receptor antagonists at OX1R and OX2R orexin receptors. Frontiers in neuroscience 33 24376396
2012 The orexin receptor OX(1)R in colon cancer: a promising therapeutic target and a new paradigm in G protein-coupled receptor signalling through ITIMs. British journal of pharmacology 33 21627633
2014 Orexin A protects cells from apoptosis by regulating FoxO1 and mTORC1 through the OX1R/PI3K/AKT signaling pathway in hepatocytes. International journal of molecular medicine 31 24807827
2010 Expression of orexin receptors 1 (OX1R) and 2 (OX2R) in the porcine hypothalamus during the oestrous cycle. Journal of physiology and pharmacology : an official journal of the Polish Physiological Society 31 20610868
2018 Ghrelin Through GHSR1a and OX1R Heterodimers Reveals a Gαs-cAMP-cAMP Response Element Binding Protein Signaling Pathway in Vitro. Frontiers in molecular neuroscience 30 30065627
2009 Expression of orexin receptors 1 (OX1R) and 2 (OX2R) in the porcine pituitary during the oestrous cycle. Animal reproduction science 30 19394166
2019 Orexin in the anxiety spectrum: association of a HCRTR1 polymorphism with panic disorder/agoraphobia, CBT treatment response and fear-related intermediate phenotypes. Translational psychiatry 26 30718541
2014 Both Ox1r and Ox2r orexin receptors contribute to the cardiovascular and locomotor components of the novelty stress response in the rat. Neuropharmacology 26 25239810
2010 Expression and localization of the orexin-1 receptor (OX1R) after traumatic brain injury in mice. Journal of molecular neuroscience : MN 26 20803175
2018 Ectopic expression of OX1R in ulcerative colitis mediates anti-inflammatory effect of orexin-A. Biochimica et biophysica acta. Molecular basis of disease 24 30251681
2007 The orexin 1 receptor (HCRTR1) gene as a susceptibility gene contributing to polydipsia-hyponatremia in schizophrenia. Neuromolecular medicine 24 17999203
2016 Orexin-A promotes Glu uptake by OX1R/PKCα/ERK1/2/GLT-1 pathway in astrocytes and protects co-cultured astrocytes and neurons against apoptosis in anoxia/hypoglycemic injury in vitro. Molecular and cellular biochemistry 23 27837432
2007 Differential distribution of orexin-A-like and orexin receptor 1 (OX1R)-like immunoreactivities in the Xenopus pituitary. Tissue & cell 23 17897692
2015 Modeling of the OX1R-orexin-A complex suggests two alternative binding modes. BMC structural biology 19 25957175
2019 Orexin/hypocretin receptor gene (HCRTR1) variation is associated with aggressive behaviour. Neuropharmacology 18 30742846
2015 Effect of orexin A on apoptosis in BGC-823 gastric cancer cells via OX1R through the AKT signaling pathway. Molecular medicine reports 17 25586545
2022 Polymorphisms and association of GRM1, GNAQ and HCRTR1 genes with seasonal reproduction and litter size in three sheep breeds. Reproduction in domestic animals = Zuchthygiene 16 35104000
2015 Absence of mutations in HCRT, HCRTR1 and HCRTR2 in patients with ROHHAD. Respiratory physiology & neurobiology 16 26555080
2018 The New *G29A and G1222A of HCRTR1, 5-HTTLPR of SLC6A4 Polymorphisms and Hypocretin-1, Serotonin Concentrations in Migraine Patients. Frontiers in molecular neuroscience 15 29922128
2022 The Orexin-A/OX1R System Induces Cell Death in Pancreatic Cancer Cells Resistant to Gemcitabine and Nab-Paclitaxel Treatment. Frontiers in oncology 11 35747788
2021 Identification and Characterization of Cannabidiol as an OX1R Antagonist by Computational and In Vitro Functional Validation. Biomolecules 10 34439801
2019 Transmembrane peptide 4 and 5 of APJ are essential for its heterodimerization with OX1R. Biochemical and biophysical research communications 10 31668922
2018 Increased training compensates for OX1R blockage-impairment of spatial memory and c-Fos expression in different cortical and subcortical areas. Behavioural brain research 10 29953904
2022 Orexin-A Reverse Bone Mass Loss Induced by Chronic Intermittent Hypoxia Through OX1R-Nrf2/HIF-1α Pathway. Drug design, development and therapy 9 35818538
2020 Orexin A associates with inflammation by interacting with OX1R/OX2R receptor and activating prepro-Orexin in cancer tissues of gastric cancer patients. Gastroenterologia y hepatologia 8 31983458
2015 Both Ox1R and Ox2R orexin receptors contribute to the cardiorespiratory response evoked from the perifornical hypothalamus. Clinical and experimental pharmacology & physiology 8 26174505
2018 [Chronic alcoholism influences the mRNA level of the orexin receptor type 1 (OX1R) in emotiogenic structures of the rat brain]. Biomeditsinskaia khimiia 7 30378563
2024 Trigeminal nerve electrical stimulation attenuates early traumatic brain injury through the TLR4/NF-κB/NLRP3 signaling pathway mediated by orexin-A/OX1R system. Aging 6 38713160
2024 A high-fat diet induced depression-like phenotype via hypocretin-HCRTR1 mediated inflammation activation. Food & function 6 39056112
2020 Association of orexin/hypocretin receptor gene (HCRTR1) with reward sensitivity, and interaction with gender. Brain research 6 32652147
2023 α-Synuclein Induced the Occurrence of RBD via Interaction with OX1R and Modulated Its Degradation. Neuromolecular medicine 4 36689149
2021 Orexin-A potentiates glycine currents by activating OX1R and IP3/Ca2+/PKC signaling pathways in spinal cord ventral horn neurons. Brain research bulletin 4 33515654
2024 Heteroaryl derivatives of suvorexant as OX1R selective PET ligand candidates: Cu-mediated 18F-fluorination of boroxines, in vitro and initial in vivo evaluation. EJNMMI research 3 39231867
2019 OX1R ANTAGONIST SB408124 ACTION AND EXTRAHYPOTHALAMIC CRF IN RATS AFTER PSYCHOTRAUMATIC EXPOSURE. Georgian medical news 3 31322529
2025 Chronic alcohol withdrawal-associated increases in VTA Hcrtr1 expression are associated with heightened nociception and anxiety-like behavior in female rats. Advances in drug and alcohol research 2 40247884
2025 Mitigation of learning and memory impairment caused by acute total sleep deprivation through OX1R/OX2R-mediated hippocampal neurogenesis in rats. Experimental gerontology 2 40318707
2025 Combined effects of HCRTR1/2 gene variants and non-genetic factors on sleep-wake transition and hemodynamic stability during propofol, dexmedetomidine, and remifentanil anesthesia. Pharmacological reports : PR 2 40439868
2024 Unraveling the function and structure impact of deleterious missense SNPs in the human OX1R receptor by computational analysis. Scientific reports 2 38191899
2023 Orexin-A/OX1R is involved in regulation of autophagy to promote cortisol secretion in adrenocortical cell. Biochimica et biophysica acta. Molecular basis of disease 1 37572990
2021 [Increase in the level of orexin receptor 1 (OX1R) mRNA in the brain structures of rats prone to impulsivity in behavior]. Biomeditsinskaia khimiia 1 34730554
2026 Chronic Paraventricular OX1R Overexpression Induces Oxidative Stress and Hypertension in Rats. bioRxiv : the preprint server for biology 0 41727139
2025 Sleep fragmentation exacerbates myocardial ischemia-reperfusion injury via hypothalamic paraventricular nucleus-resident OX1R-mediated sympathetic hyperactivity in adult mice. Annals of medicine 0 41369031
2024 Maternal exposure to Di-n-butyl phthalate (DBP) inhibit orexin receptor 1 (OX1R) expression to prevent Sertoli cells proliferation through the AKT signaling pathway. Toxicology research 0 39238804
2021 [Orexin-A inhibits γ-aminobutyric acid current of neonatal rat spinal cord ventral horn neurons by activating OX1R, OX2R and Ca2+-independent PKC]. Nan fang yi ke da xue xue bao = Journal of Southern Medical University 0 34134956

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