Affinage

CRHR1

Corticotropin-releasing factor receptor 1 · UniProt P34998

Length
415 aa
Mass
47.7 kDa
Annotated
2026-06-09
100 papers in source corpus 30 papers cited in narrative 30 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CRHR1 is a Gs-coupled receptor for CRH and related urocortin peptides that transduces stress signals into cAMP-dependent cascades governing neuroendocrine output, synaptic plasticity, and emotional behavior (PMID:10456290, PMID:27402953). Upon ligand binding it generates spatially distinct cAMP pools through both transmembrane adenylyl cyclases (tmACs) and atypical soluble adenylyl cyclase (sAC): tmAC-derived cAMP drives an acute phase of ERK1/2 activation while sAC activity sustains an internalization-dependent late phase and supports endosome-based signaling after CRHR1 endocytosis (PMID:27402953). This biphasic ERK1/2 response is built from a phase-specific machinery—early signaling through B-Raf, 14-3-3 proteins, PKA, and Rap1, and late signaling through β-arrestin2, dynamin, and vimentin, with both phases requiring calcium influx and CaMKII (PMID:23371389)—while sAC-derived cAMP separately drives ERK1/2-independent neurite elongation (PMID:28512295). CRHR1 forms heterodimers with the V1b vasopressin receptor that synergistically potentiate cAMP and inositol phosphate signaling (PMID:22301784), and its desensitization is reinforced by ligand-induced upregulation of GRK3 (PMID:12413940). In the brain, CRHR1 exerts bidirectional control of anxiety—anxiogenic via forebrain glutamatergic neurons and anxiolytic via midbrain dopaminergic neurons (PMID:21885734)—and in the hippocampus its signaling reshapes structural plasticity, LTP, and cognition through the nectin-3/afadin complex (PMID:23644483, PMID:21940453) and through NF-κB-driven autophagic degradation of BDNF (PMID:32051550). In the HPA axis, pituitary CRHR1 drives ACTH-dependent adrenal steroidogenesis, a link established both by ACTH challenge in knockout mice (PMID:11517194) and by the CRF1 antagonist crinecerfont reducing adrenal androgen excess in congenital adrenal hyperplasia (PMID:37216921). Crhr1 expression is itself dynamically controlled by CpG methylation and histone H3K9 trimethylation at its promoter and by miR-34b, mechanisms that program stress- and trauma-related phenotypes (PMID:23529784, PMID:24867333, PMID:28498394).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1999 Medium

    Established that CRHR1 is a functional, ligand-activated receptor coupled to second messengers in human cells, defining its basic signaling competence.

    Evidence cAMP accumulation and radioligand binding with peptide/non-peptide antagonists in SH-SY5Y cells, and Ca2+ imaging in keratinocytes and melanoma cells

    PMID:10456290 PMID:10816662

    Open questions at the time
    • Did not resolve which G proteins couple in which cell types
    • No distinction between cAMP pools or downstream effectors
  2. 2001 High

    Defined the requirement of CRHR1 for ACTH-driven corticosterone secretion, placing it within an intra-adrenal regulatory system beyond the classical pituitary role.

    Evidence CRHR1 knockout mice with in vivo ACTH challenge, plasma hormone measurement, and adrenal expression analysis

    PMID:11517194

    Open questions at the time
    • Intra-adrenal CRH source and the cellular signaling linking CRHR1 to steroidogenic output not detailed
    • Relative contribution of adrenal vs. pituitary CRHR1 not separated
  3. 2002 Medium

    Showed CRHR1 expression and responsiveness are ligand-regulated, via activity-dependent receptor downregulation in vivo and GRK3 upregulation as a desensitization feedback.

    Evidence Central CRH administration with binding/mRNA assays in immature rats; desensitization assay with GRK3/GRK2 mRNA and protein measurement in Y79 cells

    PMID:12093084 PMID:12413940

    Open questions at the time
    • Mechanism linking neuronal activation to receptor downregulation unresolved
    • GRK3 role inferred from expression correlation, not direct phosphorylation
  4. 2007 High

    Demonstrated that CRHR1 controls behavioral and gene-expression endpoints largely through the HPA axis/corticosterone, distinguishing central from systemic effects.

    Evidence Global CRF1 knockout plus pharmacological antagonism with opiate withdrawal scoring, CRF/dynorphin in situ hybridization, and corticosterone rescue

    PMID:17296558

    Open questions at the time
    • Did not resolve which brain circuits mediate the corticosterone-dependent effects
    • Receptor-proximal signaling not addressed
  5. 2011 High

    Resolved circuit-specific and opposing roles of CRHR1, showing forebrain glutamatergic signaling is anxiogenic while midbrain dopaminergic signaling is anxiolytic, and that brain vs. HPA CRHR1 oppose each other in stress-related behaviors.

    Evidence Cell-type-specific Cre-lox deletions with neurochemical and behavioral analysis; conditional vs. global knockout in alcohol-intake paradigms

    PMID:21885734 PMID:22113086

    Open questions at the time
    • Molecular signaling within each neuronal type not dissected
    • Connection between circuit identity and receptor coupling unknown
  6. 2011 High

    Linked forebrain CRHR1 signaling to stress-induced structural plasticity, identifying hippocampal dendritic remodeling, spine loss, and altered synaptic adhesion molecules as downstream consequences.

    Evidence Conditional forebrain CRHR1 knockout and CRH overexpression with LTP recording, spine density, dendritic morphology, and molecular readouts

    PMID:21296667 PMID:21940453

    Open questions at the time
    • Receptor-to-cytoskeleton signaling steps not fully defined
    • Causal chain from CRHR1 to neurexin-neuroligin alteration incomplete
  7. 2012 High

    Established that CRHR1 physically heterodimerizes with the V1b vasopressin receptor, providing a molecular basis for AVP+CRH signaling synergy independent of second-messenger crosstalk.

    Evidence BRET, co-immunoprecipitation, and receptor rescue with cAMP and inositol phosphate assays in HEK293 and adrenal chromaffin cells

    PMID:22301784

    Open questions at the time
    • Structural interface of the heterodimer unknown
    • Physiological tissues where the heterodimer operates not established
  8. 2013 High

    Dissected the biphasic ERK1/2 cascade downstream of CRHR1 into distinct early and late molecular machineries, and identified the nectin-afadin complex and NF-κB/BDNF autophagy as effectors of stress-induced cognitive and synaptic impairment.

    Evidence Co-IP, mass spectrometry, and pharmacological dissection in HT22 cells; conditional knockout and nectin-3 manipulation in vivo; autophagy/NF-κB pathway inhibition with BDNF and CRHR1-antagonist rescue

    PMID:23371389 PMID:23644483 PMID:32051550

    Open questions at the time
    • Spatial coordination of the two ERK phases not yet imaged in real time
    • Link between ERK signaling and nectin-afadin/BDNF effectors not directly connected
  9. 2016 High

    Identified soluble adenylyl cyclase as a distinct cAMP source enabling compartmentalized CRHR1 signaling, explaining how a single receptor generates phase- and function-specific outputs.

    Evidence Selective tmAC vs. sAC inhibition with internalization, cAMP, and ERK1/2 phosphorylation assays in pituitary and neuronal cells; sAC-dependent neurite outgrowth assays in HT22-CRHR1 cells

    PMID:27402953 PMID:28512295

    Open questions at the time
    • Mechanism activating sAC downstream of CRHR1 not established
    • Endosomal scaffold organizing sAC-dependent signaling unidentified
  10. 2018 Medium

    Demonstrated that CRHR1 expression is set by epigenetic marks—promoter CpG methylation, H3K9 trimethylation—and by miR-34b, mechanisms that program stress, trauma, and intergenerational depression phenotypes.

    Evidence Bisulfite sequencing, ChIP, DNMT3b knockdown, miR-34b manipulation, with mRNA/protein and behavioral readouts plus CRHR1-antagonist rescue across generations

    PMID:23529784 PMID:24867333 PMID:28498394 PMID:29543532

    Open questions at the time
    • Upstream signals directing the chromatin/methylation changes unclear
    • Direct demonstration that each mark causally drives CRHR1 transcription incomplete
  11. 2023 Medium

    Confirmed in humans that pituitary CRHR1 drives ACTH-dependent adrenal steroidogenesis, validating it as a therapeutic target in congenital adrenal hyperplasia.

    Evidence Phase 2 open-label clinical study of the oral CRF1 antagonist crinecerfont with ACTH and adrenal steroid measurements

    PMID:37216921

    Open questions at the time
    • No control group in single-cohort study
    • Receptor-level signaling in human pituitary not directly measured

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CRHR1's biochemical signaling repertoire (sAC/tmAC cAMP pools, biphasic ERK, V1b heterodimers) maps onto its divergent, circuit-specific behavioral and endocrine outputs remains unresolved.
  • No bridging study links cell-type-specific signaling machinery to opposing anxiety circuits
  • Structural basis of ligand selectivity and heterodimerization unknown
  • In vivo relevance of sAC compartmentalization not tested genetically

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3
Localization
GO:0005886 plasma membrane 2 GO:0005768 endosome 1
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 3
Partners
ARRB2AVPR1BBRAFDNM1
Complex memberships
CRHR1-V1b receptor heterodimer

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 CRHR1 expressed in forebrain glutamatergic and GABAergic neurons mediates anxiogenic effects, while CRHR1 in midbrain dopaminergic neurons mediates anxiolytic effects and dopamine release in the prefrontal cortex. Selective cell-type-specific deletions demonstrated bidirectional control of anxiety behavior. Conditional/cell-type-specific genetic deletion (Cre-lox), neurochemical analysis, behavioral testing Science High 21885734
2013 CRHR1 signaling reduces hippocampal nectin-3 levels after stress; suppression of nectin-3 causes spatial memory deficits and dendritic spine loss; CRH-CRHR1 interacts with the nectin-afadin complex to mediate stress-induced structural and cognitive impairments. Conditional forebrain CRHR1 knockout mice, CRH overexpression, acute stress, hippocampal nectin-3 knockdown/overexpression, spatial memory testing, spine density quantification Nature neuroscience High 23644483
2011 Forebrain CRHR1 deficiency prevents chronic stress-induced dendritic remodeling of hippocampal CA3 neurons, spatial memory deficits, and down-regulation of hippocampal glucocorticoid receptor and nectin-3 expression. Conditional forebrain CRHR1 knockout mice, chronic social defeat stress, spatial memory testing, dendritic morphology analysis, immunohistochemistry Neurobiology of disease High 21296667
2011 Forebrain CRHR1 is required for early-life stress-induced impairments in spatial learning, LTP, and dendritic spine density in hippocampal CA3; CRH overexpression in forebrain neurons reproduces these effects. CRHR1 deficiency also altered the neurexin-neuroligin complex in stressed mice. Conditional forebrain CRHR1 knockout, CRH forebrain overexpression, LTP recording, spine density counting, behavioral testing, immunofluorescence The Journal of neuroscience High 21940453
2016 CRH-activated CRHR1 generates cAMP via both transmembrane adenylyl cyclases (tmACs) and atypical soluble adenylyl cyclase (sAC). tmAC-derived cAMP is required for the acute phase of ERK1/2 activation, while sAC activity is essential for the sustained internalization-dependent phase of ERK1/2 activation and for endosome-based signaling after CRHR1 endocytosis. Pharmacological inhibition of tmACs vs. sAC, CRHR1 internalization assays, cAMP measurements, ERK1/2 phosphorylation assays in pituitary and neuronal cells The Journal of cell biology High 27402953
2013 Biphasic ERK1/2 activation downstream of CRHR1: early phase depends on cAMP, B-Raf, 14-3-3 proteins, PKA, and Rap1; late phase depends on CRHR1 internalization, β-arrestin2, dynamin, and vimentin. Both phases require calcium influx and CaMKII activity. Co-immunoprecipitation, mass spectrometry-based screening for B-Raf-associated proteins, pharmacological inhibitors, molecular tools in hippocampal HT22 cells Molecular endocrinology High 23371389
2017 Activated CRHR1 promotes neurite elongation in hippocampal HT22 cells via a sAC-dependent, ERK1/2-independent signaling cascade; sAC-generated cAMP pools (but not tmAC-generated pools) are critical for the neuritogenic effect, while both tmACs and sAC contribute to CREB phosphorylation and c-fos induction. Selective pharmacological inhibition of sAC vs. tmACs, neurite outgrowth quantification, CREB phosphorylation, c-fos reporter assays in HT22-CRHR1 cells Scientific reports Medium 28512295
2012 V1b vasopressin receptor and CRHR1 form heterodimers, demonstrated by BRET, co-immunoprecipitation, and receptor rescue experiments in HEK293 cells. Heterodimerization confers new pharmacological properties and mediates the synergistic potentiation of cAMP accumulation by AVP+CRH co-stimulation, independent of second-messenger cross-talk. Bioluminescence resonance energy transfer (BRET), co-immunoprecipitation, receptor rescue experiment, cAMP accumulation assay, inositol phosphate assay in HEK293 and adrenal chromaffin cells Molecular endocrinology High 22301784
2002 CRH binding to CRF1 (CRHR1) in immature rat brain rapidly downregulates CRF1 binding capacity in frontal cortex (within 4 h) and transiently increases CRF1 mRNA in frontal cortex and hippocampal CA3. This regulation requires both receptor occupancy and downstream neuronal activation; blocking CRH's neuroexcitant effects with pentobarbital abolishes both changes. Central CRH administration, radioligand binding assays, in situ hybridization for CRF1 mRNA, kainic acid control, pentobarbital blockade in immature rats Experimental neurology Medium 12093084
2002 CRF1 receptor desensitization induced by CRF (but not urocortin) in Y79 cells is accompanied by a 3-fold increase in GRK3 (but not GRK2) mRNA, suggesting GRK3 upregulation as a negative feedback mechanism to maximize CRHR1 desensitization during prolonged CRF exposure. cAMP accumulation assay for desensitization, RT-PCR for GRK3/GRK2 mRNA, Western blot for GRK3 protein in Y79 retinoblastoma cells Biochemical and biophysical research communications Medium 12413940
2001 CRHR1 is expressed in the mouse adrenal cortex and is required for ACTH-stimulated corticosterone secretion; in Crhr1-/- mice, intravenous ACTH fails to stimulate corticosterone release despite upregulation of ACTH receptor mRNA in adrenal cortex. Pituitary CRF2 stimulation does not induce ACTH secretion. This identifies an intra-adrenal CRH/CRHR1 regulatory system. CRHR1 knockout mouse, in vivo ACTH challenge, plasma corticosterone/ACTH measurement, RT-PCR, in situ hybridization, in vitro pituitary assays Endocrinology High 11517194
2006 CRHR1 (and CRHR2) mediate endocytosis of urocortin at the blood-brain barrier in a non-clathrin, non-caveolae-dependent manner. Both receptors increase urocortin binding and internalization; CRHR1-mediated endocytosis is blocked by astressin. Both receptors couple to cAMP production. Intracellularly degraded urocortin can be re-exocytosed as intact peptide. Overexpression in HEK293 cells, radiolabeled urocortin endocytosis assay, receptor antagonists (astressin, antisauvagine-30), pharmacological inhibitors of clathrin/caveolae, cAMP assay Molecular endocrinology Medium 17170072
1999 CRF1 receptor (CRHR1) is functionally expressed in human skin keratinocytes and melanoma cells, where CRH stimulation induces rapid, dose-dependent increases in intracellular Ca2+, blocked by the CRH antagonist alpha-helical-CRH(9-41) and by EGTA. CRH production in skin cells is enhanced by UV light and forskolin and inhibited by dexamethasone. RT-PCR, Northern blot (mRNA), immunocytochemistry (protein), intracellular Ca2+ measurements, RP-HPLC/RIA in cultured keratinocytes and melanoma cells Annals of the New York Academy of Sciences Medium 10816662
1999 CRHR1 in human neuroblastoma SH-SY5Y cells is functionally coupled to cAMP formation; CRF and related peptides (urocortin, sauvagine, urotensin I, ovine CRF) dose-dependently increase cAMP accumulation, blocked by peptide antagonists and non-peptide CRF1 antagonists (CP-154,526, antalarmin). cAMP accumulation assay, radioligand binding ([125I]Tyr0-oCRF), RT-PCR for CRF1 mRNA in SH-SY5Y cells Fundamental & clinical pharmacology Medium 10456290
2009 Alternative splicing of CRF1 (CRHR1) in human keratinocytes produces isoforms with distinct subcellular localizations: alpha and c isoforms localize to the cell membrane and activate CRE; d, f, and g isoforms are intracellular. Co-expression of alpha with d, f, or g causes intracellular retention of both isoforms (dimerization), reducing alpha's signaling activity. Soluble isoforms e and h are secreted. Isoform expression in keratinocytes, subcellular localization (immunofluorescence), CRE-reporter assay, detection of high-molecular-weight complexes (dimerization), culture medium analysis Journal of cellular physiology Medium 19006179
2011 Substance P (SP) upregulates CRHR1 mRNA and protein expression in human LAD2 mast cells via NK-1 receptor; SP-primed cells then respond to CRH by releasing IL-8, TNF, and VEGF, effects blocked by NK-1 antagonist pretreatment. Repeated CRH stimulation leads to CRHR1 downregulation and NK-1 upregulation. RT-PCR and Western blot for CRHR1 mRNA/protein, ELISA for cytokine release, NK-1 antagonist pretreatment in LAD2 mast cells The Journal of investigative dermatology Medium 22089831
2007 CRF1 receptors are expressed in colonic myenteric neurons (cholinergic and nitrergic); peripheral CRF and the selective CRF1 agonist stressin1-A activate these neurons selectively in proximal and distal colon (not stomach, duodenum, jejunum, or ileum), as shown by Fos induction in CRF1-immunoreactive myenteric neurons. Laser capture microdissection + RT-PCR, immunohistochemistry, Fos immunoreactivity after peripheral CRF/stressin1-A injection in conscious rats Neurogastroenterology and motility Medium 17973638
2004 CRF1 receptors in the central nucleus of the amygdala (CeLC) contribute to pain-related sensitization: a selective CRF1 antagonist (NBI27914) inhibited evoked responses and background activity in CeLC neurons during arthritis but had no effect under normal conditions. Extracellular single-unit electrophysiology in CeLC, intra-CeLC microdialysis of CRF1 antagonist NBI27914, kaolin/carrageenan arthritis model in anesthetized rats Journal of neurophysiology Medium 17392412
2007 Genetic inactivation (CRF1-/-) or pharmacological antagonism of CRHR1 increases and prolongs somatic expression of opiate withdrawal. Opiate-withdrawn CRF1-/- mice show aberrant CRF and dynorphin expression in PVN and striatum. Exogenous corticosterone restores normal withdrawal behavior and CRF/dynorphin gene expression patterns, indicating CRHR1's role is mediated via HPA axis-corticosterone. CRF1 global knockout, CRF1 antagonist treatment, opiate withdrawal scoring, in situ hybridization for CRF and dynorphin mRNA, corticosterone supplementation Neuron High 17296558
2011 Brain-specific (Crhr1-NestinCre) knockout mice resist stress-induced augmentation of alcohol intake and escalation in the post-dependent state, while global Crhr1 knockout shows enhanced stress-induced alcohol intake and greater escalation, indicating that extra-HPA and HPA CRHR1 signaling exert opposing effects on stress-related alcohol consumption. Brain-specific and global Crhr1 knockout mouse models, chronic intermittent vapor exposure for post-dependence, alcohol deprivation model, operant self-administration Neuropsychopharmacology High 22113086
2014 Intra-mPFC CRF1 receptor activation is tonically anxiogenic; intra-mPFC injection of CRF (75–150 pmol) produces anxiogenic-like effects blocked by the PKA inhibitor H-89, establishing that CRHR1 signaling in the mPFC modulates anxiety via the cAMP/PKA cascade. Intra-medial prefrontal cortex microinjection of CRF, CRF1 antagonist CP376395, PKA inhibitor H-89; elevated plus-maze in mice Hormones and behavior Medium 24848364
2013 CRH application to neurons induces autophagy with rapid lysosomal degradation of BDNF via the NF-κB pathway, causing synaptic loss; this effect is rescued by BDNF, specific NF-κB inhibitors, or CRHR1 antagonists in vitro, and CRHR1 antagonist treatment in vivo (after thoracic trauma) reverses hippocampal synaptic loss, behavioral deficits, and CRH/BDNF dysregulation. In vitro CRH application, autophagy assay, NF-κB pathway inhibitors, CRHR1 antagonist, BDNF rescue; in vivo thoracic trauma mouse model with CRHR1 antagonist treatment, synapse counting, behavioral testing Molecular psychiatry High 32051550
2014 miR-34b negatively regulates CRHR1 mRNA in primary hypothalamic neurons (demonstrated by bioinformatic prediction and functional validation); miR-34b overexpression in the paraventricular nucleus reduces CRHR1-dependent HPA axis hyperactivity and anxiety-like behavior after trauma. Bioinformatic miRNA target prediction, miR-34b overexpression in primary hypothalamic neurons, in vivo PVN delivery of miR-34b agomir, HPA axis hormone assay, open field and elevated plus-maze behavioral tests International journal of molecular medicine Medium 28498394
2014 Histone H3K9 trimethylation at the Crhr1 gene promoter is decreased in hypothalami of chronically stressed (CUMS) rats, correlating with elevated CRHR1 mRNA and protein expression, demonstrating that loss of a repressive chromatin mark regulates Crhr1 gene upregulation in the context of depression. Chromatin immunoprecipitation (ChIP) for H3K4me3 and H3K9me3 at Crhr1 promoter, RT-PCR, Western blot in rat CUMS model Behavioural brain research Medium 24867333
2013 Intra-CeA CRHR1 blockade reduces excessive palatable food intake and anxiety-like behavior in diet-cycled rats, while intra-BLA CRHR1 blockade reduces chow hypophagia; these distinct effects localize CRHR1 function to different amygdala sub-nuclei in compulsive eating. CRF immunostaining was increased in CeA (not BLA) of diet-cycled rats. Intra-amygdala microinfusion of CRF1 antagonist R121919, behavioral tests (food intake, anxiety), CRF immunohistochemistry Neuropsychopharmacology Medium 23748225
2022 In a CRF1-Cre-tdTomato transgenic rat, CeA CRF1+ neurons are largely GABAergic; their chemogenetic (DREADD) activation increases anxiety-like and nocifensive behaviors. CeA CRF1+ neuron membrane properties and inhibitory synaptic transmission are similar to those in CRF1-GFP mice. Transgenic CRF1-Cre rat generation, Cre-dependent DREADD viral delivery, CNO activation in vivo, electrophysiology, behavioral testing, mRNA co-localization eLife Medium 35389341
2017 CRHR1 blockade in the dorsal raphe using intra-DR injection potentiates stress-induced TPH2 (serotonin synthesis enzyme) activity in the entire DR, demonstrating that CRHR1 inhibits in vivo serotonin synthesis under stress. CRHR2 blockade in DR has the opposite effect, preventing stress-induced TPH2 activity in dorsal/caudal DR. Stereotaxic intra-DR cannula, pharmacological blockade of CRHR1 or CRHR2, 5-HTP accumulation assay as readout of TPH2 activity, acoustic startle stress in CORT-treated rats Psychoneuroendocrinology Medium 26454419
2023 Crinecerfont, an oral CRF1 receptor antagonist, reduces pituitary ACTH-driven adrenal androgen excess in adolescents with congenital adrenal hyperplasia (21-hydroxylase deficiency), demonstrating that pituitary CRHR1 activation drives ACTH-dependent adrenal steroidogenesis in vivo. Phase 2 open-label clinical study, oral crinecerfont 50mg twice daily for 14 days, circulating ACTH, 17-OHP, androstenedione, testosterone measured before and after treatment The Journal of clinical endocrinology and metabolism Medium 37216921
2013 Demethylation of specific CpG sites in the Crhr1 promoter in the hypothalamic PVN, mediated preferentially by DNMT3b, is linked to elevated CRHR1 mRNA expression and anxiety-like behavior in male offspring after gestational intermittent hypoxia, establishing epigenetic regulation of CRHR1 expression in a sex-dependent manner. Bisulfite sequencing of Crhr1 CpG islands, RT-PCR, siRNA knockdown of DNMT isoforms, behavioral testing (anxiety) in rat offspring Molecular neurobiology Medium 23529784
2018 Prenatal dexamethasone increases hippocampal CRH and CRHR1 expression in F1 and F2 offspring via hypomethylation of CpG islands in the Crhr1 promoter. CRHR1 antagonist treatment of newborn F1 offspring alleviates depression-like behavior at adulthood, establishing that CRHR1 mediates intergenerational epigenetic programming of depression. Prenatal dexamethasone rat model, RT-PCR, Western blot, bisulfite sequencing of Crhr1 promoter, postnatal CRHR1 antagonist treatment, behavioral testing across generations FASEB journal Medium 29543532

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 The rationale for corticotropin-releasing hormone receptor (CRH-R) antagonists to treat depression and anxiety. Journal of psychiatric research 489 10367986
2011 Glutamatergic and dopaminergic neurons mediate anxiogenic and anxiolytic effects of CRHR1. Science (New York, N.Y.) 259 21885734
2004 CRF1 receptor signaling pathways are involved in stress-related alterations of colonic function and viscerosensitivity: implications for irritable bowel syndrome. British journal of pharmacology 180 15100165
2007 The CRF1 receptor antagonist antalarmin attenuates yohimbine-induced increases in operant alcohol self-administration and reinstatement of alcohol seeking in rats. Psychopharmacology 165 17705061
2001 Role of CRF(1) and CRF(2) receptors in fear and anxiety. Neuroscience and biobehavioral reviews 161 11801288
2007 Interaction between CRHR1 gene and stressful life events predicts adolescent heavy alcohol use. Biological psychiatry 159 17597588
2004 The therapeutic potential of CRF1 antagonists for anxiety. Expert opinion on investigational drugs 148 15212620
2011 Forebrain CRHR1 deficiency attenuates chronic stress-induced cognitive deficits and dendritic remodeling. Neurobiology of disease 133 21296667
2011 Forebrain CRF₁ modulates early-life stress-programmed cognitive deficits. The Journal of neuroscience : the official journal of the Society for Neuroscience 133 21940453
1999 Cutaneous expression of CRH and CRH-R. Is there a "skin stress response system?". Annals of the New York Academy of Sciences 118 10816662
2010 CRF-1 antagonist and CRF-2 agonist decrease binge-like ethanol drinking in C57BL/6J mice independent of the HPA axis. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 115 20130533
2013 Nectin-3 links CRHR1 signaling to stress-induced memory deficits and spine loss. Nature neuroscience 108 23644483
2004 Corticotropin-releasing factor receptors CRF1 and CRF2 exert both additive and opposing influences on defensive startle behavior. The Journal of neuroscience : the official journal of the Society for Neuroscience 107 15269266
2004 Anxiolytic- and antidepressant-like profile of a new CRF1 receptor antagonist, R278995/CRA0450. European journal of pharmacology 106 14757135
2007 Differential effects of CRF1 and CRF2 receptor antagonists on pain-related sensitization of neurons in the central nucleus of the amygdala. Journal of neurophysiology 104 17392412
2008 Effects of CRF1-receptor and opioid-receptor antagonists on dependence-induced increases in alcohol drinking by alcohol-preferring (P) rats. Alcoholism, clinical and experimental research 101 18631323
2003 A novel water-soluble selective CRF1 receptor antagonist, NBI 35965, blunts stress-induced visceral hyperalgesia and colonic motor function in rats. Brain research 95 12957366
1999 Recent advances with the CRF1 receptor: design of small molecule inhibitors, receptor subtypes and clinical indications. Current pharmaceutical design 93 10213797
2012 CRHR1 genotypes, neural circuits and the diathesis for anxiety and depression. Molecular psychiatry 92 23147386
2010 Polymorphisms in CRHR1 and the serotonin transporter loci: gene x gene x environment interactions on depressive symptoms. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 92 20029939
2006 CRF1 receptors as a therapeutic target for irritable bowel syndrome. Current pharmaceutical design 90 17100612
2013 Behavioral, biological, and chemical perspectives on targeting CRF(1) receptor antagonists to treat alcoholism. Drug and alcohol dependence 88 23294766
2010 Therapeutic utility of non-peptidic CRF1 receptor antagonists in anxiety, depression, and stress-related disorders: evidence from animal models. Pharmacology & therapeutics 84 20826181
2011 Corticotropin-releasing hormone receptor type 1 (CRHR1) genetic variation and stress interact to influence reward learning. The Journal of neuroscience : the official journal of the Society for Neuroscience 82 21917807
2009 Interacting effects of CRHR1 gene and stressful life events on drinking initiation and progression among 19-year-olds. The international journal of neuropsychopharmacology 76 19607758
2011 Substance P (SP) induces expression of functional corticotropin-releasing hormone receptor-1 (CRHR-1) in human mast cells. The Journal of investigative dermatology 73 22089831
2013 CRF-CRF1 receptor system in the central and basolateral nuclei of the amygdala differentially mediates excessive eating of palatable food. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 69 23748225
2007 Peripheral corticotropin releasing factor (CRF) and a novel CRF1 receptor agonist, stressin1-A activate CRF1 receptor expressing cholinergic and nitrergic myenteric neurons selectively in the colon of conscious rats. Neurogastroenterology and motility 69 17973638
2002 Corticotropin-releasing hormone (CRH) downregulates the function of its receptor (CRF1) and induces CRF1 expression in hippocampal and cortical regions of the immature rat brain. Experimental neurology 63 12093084
2002 Non-peptidic CRF1 receptor antagonists for the treatment of anxiety, depression and stress disorders. Current drug targets. CNS and neurological disorders 61 12769601
2013 Chronic CRF1 receptor blockade reduces heroin intake escalation and dependence-induced hyperalgesia. Addiction biology 59 24330252
2012 Association of CRHR1 and CRHR2 with major depressive disorder and panic disorder in a Japanese population. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 59 22467522
1998 Pyrazolo[1,5-a]pyrimidine CRF-1 receptor antagonists. Bioorganic & medicinal chemistry letters 57 9873487
2016 Different cAMP sources are critically involved in G protein-coupled receptor CRHR1 signaling. The Journal of cell biology 55 27402953
2010 Emerging role of alternative splicing of CRF1 receptor in CRF signaling. Acta biochimica Polonica 55 20234885
2007 The CRF1 receptor, a novel target for the treatment of depression, anxiety, and stress-related disorders. CNS & neurological disorders drug targets 55 17511614
2001 Expression of CRHR1 and CRHR2 in mouse pituitary and adrenal gland: implications for HPA system regulation. Endocrinology 55 11517194
2011 Brain-specific inactivation of the Crhr1 gene inhibits post-dependent and stress-induced alcohol intake, but does not affect relapse-like drinking. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 54 22113086
2004 RNA structural rearrangement via unwinding and annealing by the cyanobacterial RNA helicase, CrhR. The Journal of biological chemistry 52 15542859
2005 Expression and effects of metabotropic CRF1 and CRF2 receptors in rat small intestine. American journal of physiology. Gastrointestinal and liver physiology 51 15637181
2003 Expression of CRF1 and CRF2 receptors in human cancers. The Journal of clinical endocrinology and metabolism 51 12843181
2007 Disruption of the CRF/CRF1 receptor stress system exacerbates the somatic signs of opiate withdrawal. Neuron 50 17296558
2018 The center of the emotional universe: Alcohol, stress, and CRF1 amygdala circuitry. Alcohol (Fayetteville, N.Y.) 49 30220589
2013 Gestational hypoxia induces sex-differential methylation of Crhr1 linked to anxiety-like behavior. Molecular neurobiology 49 23529784
2006 The CRF1 receptor antagonist, antalarmin, reverses isolation-induced up-regulation of dopamine D2 receptors in the amygdala and nucleus accumbens of fawn-hooded rats. The European journal of neuroscience 49 16820021
2013 CRF1 receptor signaling regulates food and fluid intake in the drinking-in-the-dark model of binge alcohol consumption. Alcoholism, clinical and experimental research 48 23398267
2005 Divergent role for CRF1 and CRF2 receptors in the modulation of visceral pain. Neurogastroenterology and motility 47 15916630
2005 The pharmacology of DMP696 and DMP904, non-peptidergic CRF1 receptor antagonists. CNS drug reviews 45 15867951
2011 Gene-environment interactions between CRHR1 variants and physical assault in suicide attempts. Genes, brain, and behavior 44 21605337
2012 V1b and CRHR1 receptor heterodimerization mediates synergistic biological actions of vasopressin and CRH. Molecular endocrinology (Baltimore, Md.) 43 22301784
2013 Corticotropin releasing hormone receptor 2 (CRHR-2) gene is associated with decreased risk and severity of posttraumatic stress disorder in women. Depression and anxiety 42 24123648
2006 Development of CRF1 receptor antagonists as antidepressants and anxiolytics: progress to date. CNS drugs 42 17044726
1997 Labelling of CRF1 and CRF2 receptors using the novel radioligand, [3H]-urocortin. Neuropharmacology 42 9423932
2009 CRF1 receptor splicing in epidermal keratinocytes: potential biological role and environmental regulations. Journal of cellular physiology 41 19006179
2017 CRF1 Receptor-Dependent Increases in Irritability-Like Behavior During Abstinence from Chronic Intermittent Ethanol Vapor Exposure. Alcoholism, clinical and experimental research 40 28833238
2017 CRHR1 promoter hypomethylation: An epigenetic readout of panic disorder? European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology 38 28233670
2014 CRHR1 links peripuberty stress with deficits in social and stress-coping behaviors. Journal of psychiatric research 38 24630468
2005 The role of CRF receptors in anxiety and depression: implications of the novel CRF1 agonist cortagine. Neuroscience and biobehavioral reviews 38 16099044
2006 Corticotropin-releasing hormone receptor (CRHR)1 and CRHR2 are both trafficking and signaling receptors for urocortin. Molecular endocrinology (Baltimore, Md.) 37 17170072
2013 Association of CRHR1 variants and posttraumatic stress symptoms in hurricane exposed adults. Journal of anxiety disorders 36 24077033
2014 Tonic modulation of anxiety-like behavior by corticotropin-releasing factor (CRF) type 1 receptor (CRF1) within the medial prefrontal cortex (mPFC) in male mice: role of protein kinase A (PKA). Hormones and behavior 35 24848364
2011 Variations in CRHR1 are associated with persistent pulmonary hypertension of the newborn. Pediatric research 35 22258127
2006 A LexA-related protein regulates redox-sensitive expression of the cyanobacterial RNA helicase, crhR. Nucleic acids research 35 16840531
2002 GRK3 regulation during CRF- and urocortin-induced CRF1 receptor desensitization. Biochemical and biophysical research communications 35 12413940
2014 CRHR1 genotype and history of maltreatment predict cortisol reactivity to stress in adolescents. Psychoneuroendocrinology 34 24703172
2015 Serotonergic systems in the balance: CRHR1 and CRHR2 differentially control stress-induced serotonin synthesis. Psychoneuroendocrinology 33 26454419
2008 Association between CRHR1 polymorphism and improved lung function in response to inhaled corticosteroid in patients with COPD. Respirology (Carlton, Vic.) 33 19210659
2004 Effects of the CRF1 antagonist SSR125543A on aggressive behaviors in hamsters. Pharmacology, biochemistry, and behavior 33 15006456
2020 A CRHR1 antagonist prevents synaptic loss and memory deficits in a trauma-induced delirium-like syndrome. Molecular psychiatry 31 32051550
2013 The CRHR1 gene, trauma exposure, and alcoholism risk: a test of G × E effects. Genes, brain, and behavior 31 23473364
2018 DNA methylation levels are associated with CRF1 receptor antagonist treatment outcome in women with post-traumatic stress disorder. Clinical epigenetics 30 30390684
2002 CRHR1 Receptor binding and lipophilicity of pyrrolopyrimidines, potential nonpeptide corticotropin-releasing hormone type 1 receptor antagonists. Bioorganic & medicinal chemistry 30 11738619
2011 Interaction between CRHR1 and BDNF genes increases the risk of recurrent major depressive disorder in Chinese population. PloS one 29 22194899
2009 An RNA helicase, CrhR, regulates the low-temperature-inducible expression of heat-shock genes groES, groEL1 and groEL2 in Synechocystis sp. PCC 6803. Microbiology (Reading, England) 29 19926653
2017 cAMP-dependent cell differentiation triggered by activated CRHR1 in hippocampal neuronal cells. Scientific reports 28 28512295
2014 Histone modifications of the Crhr1 gene in a rat model of depression following chronic stress. Behavioural brain research 28 24867333
2017 CRHR1 exacerbates the glial inflammatory response and alters BDNF/TrkB/pCREB signaling in a rat model of global cerebral ischemia: implications for neuroprotection and cognitive recovery. Progress in neuro-psychopharmacology & biological psychiatry 27 28647536
2008 5'-Upstream variants of CRHR1 and MAPT genes associated with age at onset in progressive supranuclear palsy and cortical basal degeneration. Neurobiology of disease 27 19022385
2023 Crinecerfont, a CRF1 Receptor Antagonist, Lowers Adrenal Androgens in Adolescents With Congenital Adrenal Hyperplasia. The Journal of clinical endocrinology and metabolism 26 37216921
2017 Hypothalamic CRF1 receptor mechanisms are not sufficient to account for binge-like palatable food consumption in female rats. The International journal of eating disorders 26 28833350
2013 B-Raf and CRHR1 internalization mediate biphasic ERK1/2 activation by CRH in hippocampal HT22 Cells. Molecular endocrinology (Baltimore, Md.) 26 23371389
2007 The CRF1 receptor antagonist, R121919, attenuates the severity of precipitated morphine withdrawal. European journal of pharmacology 26 17610870
2017 miR-34b attenuates trauma-induced anxiety-like behavior by targeting CRHR1. International journal of molecular medicine 25 28498394
2018 CRH/CRHR1 mediates prenatal synthetic glucocorticoid programming of depression-like behavior across 2 generations. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 24 29543532
2015 Corticotropin-releasing hormone (CRH) stimulates cocaine- and amphetamine-regulated transcript gene (CART1) expression through CRH type 1 receptor (CRHR1) in chicken anterior pituitary. Molecular and cellular endocrinology 24 26363222
2022 Generation of a CRF1-Cre transgenic rat and the role of central amygdala CRF1 cells in nociception and anxiety-like behavior. eLife 23 35389341
2014 Impaired miR449a-induced downregulation of Crhr1 expression in low-birth-weight rats. The Journal of endocrinology 23 25480379
2013 Differential expression of CRH, UCN, CRHR1 and CRHR2 in eutopic and ectopic endometrium of women with endometriosis. PloS one 23 23638035
2007 The CRF1 receptor antagonist R121919 attenuates the neuroendocrine and behavioral effects of precipitated lorazepam withdrawal. Psychopharmacology 22 17297634
2024 The diverse role of corticotropin-releasing factor (CRF) and its CRF1 and CRF2 receptors under pathophysiological conditions: Insights into stress/anxiety, depression, and brain injury processes. Neuroscience and biobehavioral reviews 21 38857667
2022 Role of CRF1 and CRF2 receptors in the lateral hypothalamus in cardiovascular and anxiogenic responses evoked by restraint stress in rats: Evaluation of acute and chronic exposure. Neuropharmacology 21 35452627
2020 Sex differences in CRF1, CRF, and CRFBP expression in C57BL/6J mouse brain across the lifespan and in response to acute stress. Journal of neurochemistry 21 32813270
2012 RNA helicase, CrhR is indispensable for the energy redistribution and the regulation of photosystem stoichiometry at low temperature in Synechocystis sp. PCC6803. Biochimica et biophysica acta 21 22575444
2009 Gene-environment interactions resulting in risk alcohol drinking behaviour are mediated by CRF and CRF1. Pharmacology, biochemistry, and behavior 21 19409922
2016 Association between FKBP5 and CRHR1 genes with suicidal behavior: A systematic review. Behavioural brain research 20 27638035
2009 8-(4-Methoxyphenyl)pyrazolo[1,5-a]-1,3,5-triazines: selective and centrally active corticotropin-releasing factor receptor-1 (CRF1) antagonists. Journal of medicinal chemistry 20 19361210
1999 Functional, endogenously expressed corticotropin-releasing factor receptor type 1 (CRF1) and CRF1 receptor mRNA expression in human neuroblastoma SH-SY5Y cells. Fundamental & clinical pharmacology 20 10456290
2014 Genetic moderation of child maltreatment effects on depression and internalizing symptoms by serotonin transporter linked polymorphic region (5-HTTLPR), brain-derived neurotrophic factor (BDNF), norepinephrine transporter (NET), and corticotropin releasing hormone receptor 1 (CRHR1) genes in African American children. Development and psychopathology 19 25422957
2010 Evidence for CRHR1 in multiple sclerosis using supervised machine learning and meta-analysis in 12,566 individuals. Human molecular genetics 19 20699326
2013 The CRHR1 gene contributes to genetic susceptibility of aggressive behavior towards others in Chinese southwest Han population. Journal of molecular neuroscience : MN 18 24243082

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