Affinage

CRHR1

Corticotropin-releasing factor receptor 1 · UniProt P34998

Length
415 aa
Mass
47.7 kDa
Annotated
2026-04-28
100 papers in source corpus 27 papers cited in narrative 27 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CRHR1 is a Gs-coupled corticotropin-releasing hormone receptor that transduces stress signals into anxiogenic behavior, neuroendocrine responses, and visceral motor output through cell-type-specific and compartmentalized cAMP signaling. Upon CRH binding, CRHR1 activates both transmembrane and soluble adenylyl cyclases to generate distinct cAMP microdomains: tmAC-derived cAMP drives acute ERK1/2 activation via a B-Raf/14-3-3/PKA/Rap1 cascade, while sAC-derived cAMP sustains internalization-dependent ERK1/2 signaling and drives neurite outgrowth; receptor internalization also engages β-arrestin2/dynamin-dependent signaling (PMID:23371389, PMID:27402953, PMID:28512295). In forebrain glutamatergic neurons, CRHR1 mediates anxiogenic neurotransmission and stress-induced dendritic remodeling through nectin-3 downregulation and NF-κB-dependent BDNF lysosomal degradation leading to synaptic loss, whereas in VTA dopaminergic neurons CRHR1 oppositely modulates anxiety and motivation via mesolimbic dopamine release (PMID:21885734, PMID:23644483, PMID:32051550, PMID:35319997). At the pituitary, CRHR1 drives ACTH secretion, and pharmacological blockade with the oral antagonist crinecerfont reduces ACTH-dependent adrenal androgen excess in congenital adrenal hyperplasia (PMID:37216921).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1997 High

    Establishing receptor subtype identity: antisense knockdown and subtype-selective autoradiography demonstrated that CRHR1 (not CRHR2) is the receptor responsible for CRF-induced anxiety and is distributed in cortical and cerebellar regions, resolving which CRF receptor subtype drives anxiogenic behavior.

    Evidence Antisense oligonucleotide knockdown with autoradiographic confirmation; radioligand autoradiography with subtype-selective displacement in rat brain and recombinant cells

    PMID:9299637 PMID:9348546 PMID:9423932

    Open questions at the time
    • Downstream intracellular signaling pathways not yet characterized
    • Cell-type specificity of anxiogenic action unknown
    • Endogenous ligand hierarchy (CRH vs. urocortin) at CRHR1 in vivo unresolved
  2. 2000 High

    Confirming CRHR1 as the pituitary ACTH-releasing receptor: CRF-saporin selectively killed CRF1-expressing cells and suppressed CRF-induced ACTH release from native pituitary cells, rescued by CRF1-selective antagonists, establishing CRHR1 as the functional mediator of pituitary corticotroph activation.

    Evidence Cytotoxicity assay in CRF1/CRF2-transfected cells; ACTH release from cultured rat pituitary cells with pharmacological rescue

    PMID:10650928

    Open questions at the time
    • Signaling mechanism downstream of CRHR1 in corticotrophs not dissected
    • Relevance to human pituitary pathology not tested
  3. 2003 High

    Extending CRHR1 function to peripheral stress responses: selective CRF1 antagonism blocked both stress-induced visceral hyperalgesia and CRF-driven colonic transit stimulation, while central CRF1 mediated colonic (not gastric) effects, establishing CRHR1 as the subtype mediating gut-brain axis stress responses.

    Evidence Selective CRF1 antagonist with receptor occupancy confirmed by autoradiography; colonic transit and visceromotor response assays; i.c.v. agonist/antagonist studies in conscious mice

    PMID:11960782 PMID:12957366 PMID:14755002

    Open questions at the time
    • Precise neuronal circuits mediating central CRF1-to-gut signaling not mapped
    • Whether peripheral CRHR1 on enteric neurons acts independently of central input not resolved
  4. 2004 High

    Broadening the behavioral repertoire: CRHR1 was shown to be required for CRF-induced startle potentiation, prepulse inhibition deficits, ethanol withdrawal anxiety, and amygdala pain sensitization, generalizing its role beyond classical anxiety to sensorimotor gating and pain processing.

    Evidence CRF1 knockout mice and pharmacological antagonism; acoustic startle/PPI; social interaction test during ethanol withdrawal; single-unit electrophysiology in CeLC with local antagonist delivery

    PMID:14751471 PMID:15269266 PMID:17392412

    Open questions at the time
    • Intracellular pathways linking CRHR1 to amygdala neuronal sensitization not defined
    • Whether CRHR1 contributions to pain differ between acute and chronic models unresolved
  5. 2009 Medium

    Defining splice-variant biology and extraneural expression: CRHR1 splice variants were shown to differ in membrane trafficking and signaling capacity in skin keratinocytes, with only CRF1α reaching the plasma membrane and activating CRE, while other isoforms cause intracellular retention via dimerization — revealing a post-transcriptional regulatory layer.

    Evidence Fluorescence localization of tagged isoforms; CRE-reporter assays; co-expression molecular weight analysis in keratinocytes

    PMID:10816662 PMID:19006179

    Open questions at the time
    • Physiological relevance of intracellular isoform retention not tested in vivo
    • Whether isoform-ratio changes under UV/stress functionally alter CRH responsiveness unresolved
    • Mechanism of dimerization-induced retention not structurally characterized
  6. 2011 High

    Resolving the cell-type paradox: conditional deletion showed CRHR1 in forebrain glutamatergic neurons drives anxiety and amygdala/hippocampal neurotransmission, while CRHR1 in VTA dopaminergic neurons is anxiolytic and promotes prefrontal dopamine release — demonstrating that the same receptor produces opposite behavioral outputs depending on neuronal identity.

    Evidence Cre/lox conditional Crhr1 knockout in glutamatergic, GABAergic, dopaminergic, and serotonergic neurons; anxiety behavior, electrophysiology, and dopamine release measurements

    PMID:21885734

    Open questions at the time
    • Whether the opposing effects converge on a shared downstream molecular pathway unknown
    • Contribution of CRHR1 in GABAergic and serotonergic populations functionally minimal but not fully excluded
  7. 2013 High

    Identifying the downstream structural effector in hippocampus: CRH-CRHR1 signaling was shown to reduce nectin-3 in hippocampus, causing dendritic spine loss and spatial memory deficits that could be rescued by nectin-3 overexpression — providing a molecular bridge from receptor activation to synaptic structural damage.

    Evidence Conditional CRHR1 knockout, CRH-overexpressing transgenics, viral nectin-3 manipulation; dendritic spine analysis and spatial memory testing

    PMID:21296667 PMID:23644483

    Open questions at the time
    • Signaling steps between CRHR1 activation and nectin-3 downregulation not mapped
    • Whether nectin-3 reduction is transcriptional or post-translational not defined
  8. 2013 High

    Dissecting biphasic ERK1/2 signaling: the early phase of CRH-CRHR1-induced ERK1/2 activation was shown to require cAMP/B-Raf/14-3-3/PKA/Rap1, while a sustained late phase depends on β-arrestin2, dynamin, and vimentin-mediated receptor internalization — establishing a two-phase signaling model for CRHR1.

    Evidence Pharmacological inhibitors, dominant negatives, siRNA, MS-based B-Raf interactome, co-IP and kinase assays in HT22 hippocampal cells

    PMID:23371389

    Open questions at the time
    • Whether both phases operate in primary neurons in vivo not confirmed
    • Identity of the endosomal signaling complex components beyond β-arrestin2/dynamin incomplete
  9. 2016 High

    Revealing compartmentalized cAMP generation: CRHR1 was found to activate both transmembrane (tmAC) and soluble (sAC) adenylyl cyclases, with tmAC contributing to acute ERK1/2 activation and sAC uniquely required for sustained post-endocytic ERK1/2 signaling — explaining how a single receptor generates functionally distinct cAMP microdomains.

    Evidence Selective tmAC inhibitor (MDL-12,330A) and sAC inhibitor (KH7); ERK1/2 phosphorylation and cAMP measurements; endosome fractionation

    PMID:27402953

    Open questions at the time
    • Physical association of sAC with the endosomal CRHR1 complex not demonstrated
    • Whether sAC activation is direct or mediated by calcium influx not resolved
  10. 2017 High

    Linking compartmentalized signaling to cellular outcomes: sAC-derived (not tmAC-derived) cAMP was shown to be critical for CRH-CRHR1-induced neurite elongation, while both sources contribute to CREB/c-fos activation, demonstrating that the two cAMP pools drive distinct functional outputs from the same receptor.

    Evidence Selective sAC/tmAC inhibitors; neurite length, CREB phosphorylation, and c-fos expression in HT22-CRHR1 cells

    PMID:28512295

    Open questions at the time
    • Downstream effectors of sAC-cAMP that specifically mediate neurite outgrowth unknown
    • Whether this sAC-dependent neuritogenesis occurs in primary hippocampal neurons not tested
  11. 2017 High

    Connecting CRHR1 to autophagy and BDNF degradation: CRH-CRHR1 signaling in hippocampal neurons was shown to induce NF-κB-dependent autophagy that drives BDNF lysosomal degradation and synaptic loss, reversible by CRHR1 antagonism in vivo — providing a mechanistic pathway from stress receptor activation to synaptopathy.

    Evidence In vitro CRH treatment with autophagy/lysosomal and NF-κB inhibitors; in vivo CRHR1 antagonist in trauma model; synapse counting, BDNF measurement, memory testing

    PMID:32051550

    Open questions at the time
    • Which NF-κB subunits are activated and how CRHR1 engages this pathway not defined
    • Relationship between sAC/tmAC signaling and the NF-κB/autophagy axis not tested
  12. 2022 High

    Demonstrating CRHR1 as an individual-difference switch for motivation: CRHR1 expression levels in VTA dopamine neurons were found to vary with trait anxiety and to determine whether stress facilitates or dampens effortful motivation, extending the cell-type-specific model to inter-individual variation in stress coping.

    Evidence Natural anxiety trait variation; CRHR1 quantification in VTA DA neurons; cell-type-specific manipulation; operant motivation task; in vivo DA neuron electrophysiology

    PMID:35319997

    Open questions at the time
    • Mechanism setting CRHR1 expression levels in VTA DA neurons not identified
    • Whether CRHR1 expression variation in VTA translates to human anxiety phenotypes unknown
  13. 2023 High

    Clinical translation to endocrine disease: the oral CRHR1 antagonist crinecerfont reduced ACTH, 17-OHP, and androstenedione in congenital adrenal hyperplasia patients, confirming that pituitary CRHR1 drives pathological androgen excess in 21-hydroxylase deficiency and validating CRHR1 as a therapeutic target.

    Evidence Open-label phase 2 clinical trial with serial endocrine measurements

    PMID:37216921

    Open questions at the time
    • Long-term efficacy and safety not established
    • Whether CRHR1 blockade affects other pituitary axes in CAH patients not reported

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include how CRHR1 engages the NF-κB/autophagy pathway, what molecular mechanism connects sAC-derived cAMP to neuritogenesis, how CRHR1 splice-variant ratios regulate receptor surface availability in vivo, and what sets individual CRHR1 expression levels in VTA dopamine neurons that determine stress-coping strategy.
  • No structural model of CRHR1-sAC or CRHR1-β-arrestin2 complex
  • In vivo relevance of tmAC vs. sAC signaling dichotomy not tested
  • Epigenetic regulation of CRHR1 (DNA methylation, H3K9me3) demonstrated only correlationally

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0009975 cyclase activity 2
Localization
GO:0005886 plasma membrane 3 GO:0005768 endosome 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-112316 Neuronal System 2 R-HSA-1643685 Disease 1 R-HSA-9612973 Autophagy 1
Partners
ADCY10ARRB2BRAFDNM1PVRL3VIMYWHAZ

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 CRF1 receptor (CRHR1) mediates anxiogenic-like behavior: antisense oligonucleotide knockdown of CRF1 (but not CRF2) receptors produced anxiolytic-like effects in the Defensive Withdrawal test, establishing CRF1 as the receptor subtype responsible for CRF-induced anxiety. Antisense oligonucleotide knockdown confirmed by autoradiography; behavioral testing in Defensive Withdrawal and swim stressor models Regulatory peptides High 9299637
1997 CRF1 and CRF2 receptors have distinct regional distributions in rat brain: CRF1 localizes to cerebellum and cortical areas, while CRF2 localizes to lateral septal nucleus, entorhinal cortex, and amygdaloid/hypothalamic regions, as demonstrated by autoradiographic binding with subtype-selective ligands. Autoradiography using [125I]sauvagine with differential displacement by ovine CRF to discriminate subtypes; pharmacological characterization in CRF1-transfected Sf9 cells and CRF2-transfected CHO cells Neuropsychopharmacology High 9348546
1997 CRF1 receptor binds urocortin, sauvagine, urotensin I, and CRF with high affinity (Ki ≤10 nM), and is labeled by [3H]-urocortin; non-peptidic CRF antagonists (CP 154,526, SC 241) inhibit CRF1 but not CRF2 binding. Radioligand binding ([3H]-urocortin) in recombinant CRF1-transfected cells; competition binding with peptide and non-peptide ligands Neuropharmacology High 9423932
1999 CRHR1 is expressed in skin (mouse and human) and is functional: CRH application to keratinocytes and melanoma cells induces rapid, dose-dependent increases in intracellular Ca2+, blocked by the CRH antagonist alpha-helical-CRH(9-41) and depletion of extracellular calcium with EGTA. RT-PCR, Northern blot (CRF-R1 mRNA); immunocytochemistry (protein); intracellular Ca2+ measurement after CRH stimulation; pharmacological blockade Annals of the New York Academy of Sciences Medium 10816662
2000 CRF-saporin conjugate selectively kills CRF1 receptor-expressing cells but not CRF2-expressing cells, and suppresses CRF-induced ACTH release from pituitary cells expressing native CRF1 receptors; toxicity is blocked by CRF1/CRF2 peptide antagonist and by selective non-peptide CRF1 antagonist NBI 27914. Cytotoxicity assay in CRF1- and CRF2-transfected L cells; ACTH release assay in cultured rat pituitary cells; pharmacological rescue with antagonists Endocrinology High 10650928
2002 Peripheral CRF activates myenteric cholinergic neurons in the proximal colon via CRF1 receptors: intraperitoneal CRF induced Fos expression in choline acetyltransferase-positive (cholinergic) myenteric neurons, blocked by CRF1/CRF2 antagonist astressin and selective CRF1 antagonist CP-154,526, but not by atropine. Fos immunohistochemistry on colonic longitudinal muscle/myenteric plexus whole mounts; double-labeling with ChAT and NADPH-diaphorase; pharmacological blockade with selective antagonists American journal of physiology. Gastrointestinal and liver physiology High 11960782
2003 CRF1 receptor mediates stress-induced visceral hyperalgesia and colonic transit stimulation: selective CRF1 antagonist NBI 35965 blocked CRF-induced shortening of colonic transit and abolished water avoidance stress-induced visceromotor hyperalgesia to colorectal distention. Ex vivo receptor autoradiography (CRF1 occupancy); in vivo colonic transit assay; visceromotor response to colorectal distention with and without CRF1 antagonist pretreatment Brain research High 12957366
2004 Brain CRF1 receptors mediate stimulation of colonic transit by central CRF, urocortins, and restraint stress, while CRF2 receptors mediate inhibition of gastric transit: selective CRF1 antagonist NBI-35965 blocked colonic effects, while CRF2 antagonist astressin2-B blocked gastric effects. Intracerebroventricular injection of selective agonists/antagonists; gastric emptying and colonic bead transit assays in conscious mice The Journal of physiology High 14755002
2004 CRHR1 mediates ethanol withdrawal-induced anxiety: CRF1 receptor antagonist CRA1000 blocked reduced social interaction (anxiety-like behavior) during multiple ethanol withdrawal, while CRF2 antagonist antisauvagine-30 was without effect. Pharmacological antagonism (CRF1 vs. CRF2 selective antagonists) during ethanol withdrawal; social interaction test Pharmacology, biochemistry, and behavior Medium 14751471
2004 CRF1 receptors in the central nucleus of the amygdala (CeLC) contribute to pain-related sensitization: selective CRF1 antagonist NBI27914 inhibited evoked responses and background activity in arthritis pain model neurons, whereas CRF2 antagonist had no effect in arthritis but increased responses under normal conditions. Extracellular single-unit recordings from CeLC neurons in anesthetized rats; intra-CeLC microdialysis of selective CRF1/CRF2 antagonists; kaolin/carrageenan arthritis model Journal of neurophysiology High 17392412
2004 CRF1 receptors mediate CRF-induced increases in startle magnitude and CRF-induced deficits in prepulse inhibition (PPI): pharmacological CRF1 blockade reversed both effects; in CRF1 knockout mice, CRF had no effect on startle and increased PPI, supporting CRF1 as required for these stress-related sensory gating effects. CRF1 pharmacological antagonism and CRF1 knockout mice; acoustic startle and PPI measurement The Journal of neuroscience High 15269266
2009 Swim stress-induced expression of relaxin-3 in nucleus incertus neurons is mediated via CRF1 receptors: systemic CRF1 antagonist antalarmin blocked the rapid stress-induced upregulation of relaxin-3 mRNA and hnRNA in CRF1-expressing NI neurons. In situ hybridization with exon- and intron-directed probes; systemic CRF1 antagonist pretreatment; forced swim stress paradigm Neuropharmacology Medium 19560474
2009 CRF1 receptor splice variants (alpha, beta, c, d, e, f, g, h) are expressed in human skin keratinocytes in a cell density- and UV-dependent manner. Only CRF1alpha and CRF1c localize to the plasma membrane, with CRF1alpha efficiently activating cAMP response element (CRE). Other isoforms (d, f, g) have intracellular localization; co-expression with CRF1alpha causes intracellular retention of both isoforms, suggesting dimerization confirmed by high-molecular-weight complexes. Fluorescence localization of isoform-tagged constructs; CRE-reporter assay; co-expression and molecular weight analysis; UV irradiation and density manipulation Journal of cellular physiology Medium 19006179
2011 CRHR1 in forebrain glutamatergic neurons mediates anxiogenic effects and amygdala/hippocampal neurotransmission, while CRHR1 in midbrain dopaminergic neurons mediates anxiolytic effects and dopamine release in the prefrontal cortex: demonstrated by cell type-specific conditional Crhr1 deletions. Cre/lox conditional knockout of CRHR1 in glutamatergic, GABAergic, dopaminergic, and serotonergic neurons; behavioral anxiety testing; electrophysiology; dopamine release measurement Science (New York, N.Y.) High 21885734
2011 Forebrain CRHR1 is required for chronic stress-induced dendritic remodeling of CA3 pyramidal neurons and spatial memory deficits: forebrain-specific Crhr1 knockout mice were protected from chronic social defeat stress-induced dendritic complexity reduction and showed normal nectin-3 expression and glucocorticoid receptor levels in hippocampus. Conditional forebrain-specific Crhr1 knockout mice; chronic social defeat stress; dendritic morphology analysis; spatial memory testing; nectin-3 and GR immunohistochemistry Neurobiology of disease High 21296667
2011 Substance P induces expression of functional CRHR1 in human mast cells via NK-1 receptor activation: SP treatment increased CRHR1 mRNA and protein in LAD2 mast cells, and subsequent CRH stimulation of SP-primed cells induced IL-8, TNF, and VEGF release; effects blocked by NK-1 antagonist. CRH also induces NK-1 gene expression, and repeated CRH stimulation downregulates CRHR1 and upregulates NK-1. RT-PCR and protein expression; cytokine ELISA after SP priming and CRH stimulation; NK-1 antagonist blockade; gene expression profiling The Journal of investigative dermatology Medium 22089831
2013 CRH-CRHR1 signaling reduces hippocampal nectin-3 levels, linking CRHR1 to stress-induced spine loss and spatial memory deficits: CRHR1 inactivation attenuated early-life stress-induced nectin-3 reduction; CRH overexpression in forebrain mimicked the reduction; suppression of hippocampal nectin-3 caused dendritic spine loss and memory deficits; enhancing nectin-3 rescued these effects. Conditional CRHR1 knockout; CRH forebrain overexpression transgenic mice; acute stress; western blot/IHC for nectin-3; viral nectin-3 knockdown and overexpression; dendritic spine analysis; spatial memory testing Nature neuroscience High 23644483
2013 B-Raf and CRHR1 internalization mediate biphasic ERK1/2 activation by CRH in hippocampal neurons: an early cAMP/B-Raf-dependent phase requires 14-3-3 proteins, PKA, and Rap1; a late phase requires CRHR1 internalization and β-arrestin2, dynamin, and vimentin. Both phases require calcium influx and are affected by CaMKII inactivation. Pharmacological inhibitors; dominant negative constructs; siRNA knockdown; mass-spectrometry-based B-Raf interactome screen; co-immunoprecipitation; kinase activity assays; dynamin/β-arrestin2 overexpression in hippocampal HT22 cells Molecular endocrinology (Baltimore, Md.) High 23371389
2014 miR-449a negatively regulates CRHR1 mRNA in the anterior pituitary; impaired miR-449a induction in low-birth-weight rats leads to dysregulated CRHR1 expression and prolonged HPA axis activation after restraint stress. GAS5 expression inhibits glucocorticoid receptor binding, contributing to impaired miR-449a/CRHR1 regulation. RT-PCR for miR449a and CRHR1 in anterior pituitary; plasma corticosterone RIA; GAS5 expression analysis; comparison of normal vs. low-birth-weight rat offspring The Journal of endocrinology Medium 25480379
2014 miR-34b negatively regulates CRHR1 mRNA in primary hypothalamic neurons; overexpression of miR-34b in the paraventricular nucleus decreased CRHR1 levels, reduced HPA axis hyperactivity (ACTH, corticosterone), and attenuated trauma-induced anxiety-like behavior. Bioinformatic target prediction; miR-34b overexpression by agomir delivery into PVN; radioimmunoassay for HPA hormones; open field and elevated plus maze behavioral tests International journal of molecular medicine Medium 28498394
2016 CRHR1 activates cAMP signaling through two distinct adenylyl cyclase sources: transmembrane adenylyl cyclases (tmACs) and the atypical soluble adenylyl cyclase (sAC). Both tmAC- and sAC-generated cAMP are required for the acute phase of CRH-stimulated ERK1/2 activation, while only sAC activity is essential for the sustained, internalization-dependent phase of ERK1/2 activation and cAMP generation after endocytosis. Pharmacological inhibitors of tmACs (MDL-12,330A) and sAC (KH7); CRHR1 internalization assays; ERK1/2 phosphorylation; cAMP measurement; endosome fractionation The Journal of cell biology High 27402953
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 cAMP) are critical for the neuritogenic effect, while both tmAC and sAC contribute to CRH-mediated CREB phosphorylation and c-fos induction. Selective inhibitors of sAC and tmACs; neurite length measurement; CREB phosphorylation and c-fos expression assays in HT22-CRHR1 hippocampal cells Scientific reports High 28512295
2017 CRHR1 blockade prevents CRH-induced neuronal autophagy, BDNF lysosomal degradation via the NF-κB pathway, and subsequent synaptic loss in hippocampal neurons: in vitro CRH application induced autophagy and rapid BDNF degradation rescued by CRHR1 antagonists and NF-κB inhibitors; in vivo CRHR1 antagonist reversed trauma-induced synaptic loss, BDNF reduction, and memory deficits. In vitro CRH treatment of hippocampal neurons; autophagy and lysosomal pathway inhibitors; BDNF measurement; NF-κB pathway analysis; in vivo thoracic trauma mouse model with chronic CRHR1 antagonist; synapse counting by immunohistochemistry; memory testing Molecular psychiatry High 32051550
2022 CRHR1 in VTA dopamine neurons acts as a switching mechanism determining whether acute stress facilitates or dampens effortful motivation: CRHR1 expression levels in VTA DA neurons differ by individual anxiety level (high vs. low anxious rats), and these differences mediate divergent stress effects on motivated behavior and mesolimbic DA neuron function. Natural variation in trait anxiety; CRHR1 expression quantification in VTA DA neurons; cell-type specific CRHR1 manipulation; operant effort-based motivation task; in vivo electrophysiology of mesolimbic DA neurons Science advances High 35319997
2023 Crinecerfont, an oral CRF1 receptor antagonist, reduces pituitary ACTH drive in congenital adrenal hyperplasia (CAH): treatment for 14 days produced median reductions of 57% ACTH, 69% 17-OHP, and 58% androstenedione, confirming that CRHR1 at the pituitary level drives ACTH-dependent androgen excess in 21-hydroxylase deficiency. Open-label phase 2 clinical trial; serial measurements of ACTH, 17-OHP, androstenedione, and testosterone before and after crinecerfont The Journal of clinical endocrinology and metabolism High 37216921
2014 Histone H3K9 trimethylation (repressive mark) at the Crhr1 gene promoter is decreased in the hypothalamus of chronically stressed rats, correlating with increased CRHR1 mRNA and protein expression, suggesting that epigenetic derepression drives Crhr1 upregulation in depression. Chromatin immunoprecipitation (ChIP) for H3K4me3 and H3K9me3; RT-PCR and western blot for CRHR1; chronic unpredictable mild stress (CUMS) rat model Behavioural brain research Medium 24867333
2013 Gestational intermittent hypoxia induces sex-dependent (male-specific) demethylation at CpG sites in the Crhr1 promoter, linked to increased CRHR1 mRNA in the PVN and anxiety-like behavior in adult offspring; DNMT3b is required for Crhr1 methylation. Bisulfite sequencing for CpG methylation; RT-PCR for CRHR1 mRNA; siRNA knockdown of DNMT1, DNMT3a, DNMT3b; gestational hypoxia animal model; behavioral testing Molecular neurobiology Medium 23529784

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 488 10367986
2007 Upregulation of voluntary alcohol intake, behavioral sensitivity to stress, and amygdala crhr1 expression following a history of dependence. Biological psychiatry 270 17585886
2011 Glutamatergic and dopaminergic neurons mediate anxiogenic and anxiolytic effects of CRHR1. Science (New York, N.Y.) 258 21885734
2009 Protective effect of CRHR1 gene variants on the development of adult depression following childhood maltreatment: replication and extension. Archives of general psychiatry 204 19736354
1997 Corticotropin-releasing factor CRF1, but not CRF2, receptors mediate anxiogenic-like behavior. Regulatory peptides 198 9299637
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
2007 Interaction between CRHR1 gene and stressful life events predicts adolescent heavy alcohol use. Biological psychiatry 158 17597588
2006 Genetic association of the human corticotropin releasing hormone receptor 1 (CRHR1) with binge drinking and alcohol intake patterns in two independent samples. Molecular psychiatry 156 16550213
2004 Central CRF, urocortins and stress increase colonic transit via CRF1 receptors while activation of CRF2 receptors delays gastric transit in mice. The Journal of physiology 148 14755002
2004 The therapeutic potential of CRF1 antagonists for anxiety. Expert opinion on investigational drugs 147 15212620
2009 Sequence variations of ABCB1, SLC6A2, SLC6A3, SLC6A4, CREB1, CRHR1 and NTRK2: association with major depression and antidepressant response in Mexican-Americans. Molecular psychiatry 136 19844206
2004 Modulation of multiple ethanol withdrawal-induced anxiety-like behavior by CRF and CRF1 receptors. Pharmacology, biochemistry, and behavior 136 14751471
1997 Autoradiographic localization of CRF1 and CRF2 binding sites in adult rat brain. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 136 9348546
2011 Forebrain CRHR1 deficiency attenuates chronic stress-induced cognitive deficits and dendritic remodeling. Neurobiology of disease 132 21296667
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 113 20130533
2013 Nectin-3 links CRHR1 signaling to stress-induced memory deficits and spine loss. Nature neuroscience 108 23644483
2009 Swim stress excitation of nucleus incertus and rapid induction of relaxin-3 expression via CRF1 activation. Neuropharmacology 107 19560474
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
2012 Genetic association of FKBP5 and CRHR1 with cortisol response to acute psychosocial stress in healthy adults. Psychopharmacology 105 23274505
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 102 17392412
2005 Buprenorphine and a CRF1 antagonist block the acquisition of opiate withdrawal-induced conditioned place aversion in rats. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 101 15138444
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
2012 CRHR1 genotypes, neural circuits and the diathesis for anxiety and depression. Molecular psychiatry 92 23147386
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 83 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
2008 Combined effects of exonic polymorphisms in CRHR1 and AVPR1B genes in a case/control study for panic disorder. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 81 18384079
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
2002 Peripheral CRF activates myenteric neurons in the proximal colon through CRF(1) receptor in conscious rats. American journal of physiology. Gastrointestinal and liver physiology 66 11960782
2012 Effects of CB1 and CRF1 receptor antagonists on binge-like eating in rats with limited access to a sweet fat diet: lack of withdrawal-like responses. Physiology & behavior 62 22776620
2002 Non-peptidic CRF1 receptor antagonists for the treatment of anxiety, depression and stress disorders. Current drug targets. CNS and neurological disorders 61 12769601
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
2013 Chronic CRF1 receptor blockade reduces heroin intake escalation and dependence-induced hyperalgesia. Addiction biology 58 24330252
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
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
2012 Variation in the corticotropin-releasing hormone receptor 1 (CRHR1) gene influences fMRI signal responses during emotional stimulus processing. The Journal of neuroscience : the official journal of the Society for Neuroscience 53 22378896
2007 The CRF1 receptor, a novel target for the treatment of depression, anxiety, and stress-related disorders. CNS & neurological disorders drug targets 52 17511614
2004 RNA structural rearrangement via unwinding and annealing by the cyanobacterial RNA helicase, CrhR. The Journal of biological chemistry 52 15542859
2003 Expression of CRF1 and CRF2 receptors in human cancers. The Journal of clinical endocrinology and metabolism 51 12843181
2013 Gestational hypoxia induces sex-differential methylation of Crhr1 linked to anxiety-like behavior. Molecular neurobiology 49 23529784
2007 Disruption of the CRF/CRF1 receptor stress system exacerbates the somatic signs of opiate withdrawal. Neuron 49 17296558
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
2018 The center of the emotional universe: Alcohol, stress, and CRF1 amygdala circuitry. Alcohol (Fayetteville, N.Y.) 48 30220589
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
2009 Depression in suicidal males: genetic risk variants in the CRHR1 gene. Genes, brain, and behavior 48 19220485
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
2004 Anxiolytic-like effects of the corticotropin-releasing factor1 (CRF1) antagonist DMP904 [4-(3-pentylamino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-pyrazolo-[1,5-a]-pyrimidine] administered acutely or chronically at doses occupying central CRF1 receptors in rats. The Journal of pharmacology and experimental therapeutics 45 14742750
2011 Gene-environment interactions between CRHR1 variants and physical assault in suicide attempts. Genes, brain, and behavior 44 21605337
1997 Labelling of CRF1 and CRF2 receptors using the novel radioligand, [3H]-urocortin. Neuropharmacology 42 9423932
2015 Allelic variation in CRHR1 predisposes to panic disorder: evidence for biased fear processing. Molecular psychiatry 41 26324098
2009 CRF1 receptor splicing in epidermal keratinocytes: potential biological role and environmental regulations. Journal of cellular physiology 41 19006179
2006 Development of CRF1 receptor antagonists as antidepressants and anxiolytics: progress to date. CNS drugs 40 17044726
2005 The role of CRF receptors in anxiety and depression: implications of the novel CRF1 agonist cortagine. Neuroscience and biobehavioral reviews 37 16099044
2022 Opposite effects of stress on effortful motivation in high and low anxiety are mediated by CRHR1 in the VTA. Science advances 36 35319997
2014 CRHR1 links peripuberty stress with deficits in social and stress-coping behaviors. Journal of psychiatric research 36 24630468
2013 Differential effect of orexin-1 and CRF-1 antagonism on stress circuits: a fMRI study in the rat with the pharmacological stressor Yohimbine. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 36 23736277
2013 Association of CRHR1 variants and posttraumatic stress symptoms in hurricane exposed adults. Journal of anxiety disorders 36 24077033
2015 Chronic intermittent ethanol exposure in mice leads to an up-regulation of CRH/CRHR1 signaling. Alcoholism, clinical and experimental research 35 25833034
2011 Variations in CRHR1 are associated with persistent pulmonary hypertension of the newborn. Pediatric research 34 22258127
2006 A LexA-related protein regulates redox-sensitive expression of the cyanobacterial RNA helicase, crhR. Nucleic acids research 34 16840531
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
2015 Serotonergic systems in the balance: CRHR1 and CRHR2 differentially control stress-induced serotonin synthesis. Psychoneuroendocrinology 32 26454419
2009 Synthesis and structure-activity relationships of 8-(pyrid-3-yl)pyrazolo[1,5-a]-1,3,5-triazines: potent, orally bioavailable corticotropin releasing factor receptor-1 (CRF1) antagonists. Journal of medicinal chemistry 32 19361209
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
2013 Characterization of the T-cell-mediated immune response against the Aspergillus fumigatus proteins Crf1 and catalase 1 in healthy individuals. The Journal of infectious diseases 31 23698813
2018 DNA methylation levels are associated with CRF1 receptor antagonist treatment outcome in women with post-traumatic stress disorder. Clinical epigenetics 30 30390684
2007 CRF1 not glucocorticoid receptors mediate prepulse inhibition deficits in mice overexpressing CRF. Biological psychiatry 30 17716630
2011 Interaction between CRHR1 and BDNF genes increases the risk of recurrent major depressive disorder in Chinese population. PloS one 29 22194899
2017 cAMP-dependent cell differentiation triggered by activated CRHR1 in hippocampal neuronal cells. Scientific reports 28 28512295
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
2014 Histone modifications of the Crhr1 gene in a rat model of depression following chronic stress. Behavioural brain research 27 24867333
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
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
2011 Proteomics reveals a role for the RNA helicase crhR in the modulation of multiple metabolic pathways during cold acclimation of Synechocystis sp. PCC6803. Journal of proteome research 26 21678991
2010 Discovery of NBI-77860/GSK561679, a potent corticotropin-releasing factor (CRF1) receptor antagonist with improved pharmacokinetic properties. Bioorganic & medicinal chemistry letters 26 21074436
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
2023 Crinecerfont, a CRF1 Receptor Antagonist, Lowers Adrenal Androgens in Adolescents With Congenital Adrenal Hyperplasia. The Journal of clinical endocrinology and metabolism 24 37216921
2016 Early postnatal stress suppresses the developmental trajectory of hippocampal pyramidal neurons: the role of CRHR1. Brain structure & function 24 26792004
2014 Local corticotropin releasing hormone (CRH) signals to its receptor CRHR1 during postnatal development of the mouse olfactory bulb. Brain structure & function 24 25224546
2014 Impaired miR449a-induced downregulation of Crhr1 expression in low-birth-weight rats. The Journal of endocrinology 22 25480379
2007 The CRF1 receptor antagonist R121919 attenuates the neuroendocrine and behavioral effects of precipitated lorazepam withdrawal. Psychopharmacology 22 17297634
2020 Anxiogenesis induced by social defeat in male mice: Role of nitric oxide, NMDA, and CRF1 receptors in the medial prefrontal cortex and BNST. Neuropharmacology 21 32006904
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
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
2009 Synthesis, structure-activity relationships, and in vivo evaluation of N3-phenylpyrazinones as novel corticotropin-releasing factor-1 (CRF1) receptor antagonists. Journal of medicinal chemistry 20 19552437
2018 The involvement of CRF1 receptor within the basolateral amygdala and dentate gyrus in the naloxone-induced conditioned place aversion in morphine-dependent mice. Progress in neuro-psychopharmacology & biological psychiatry 19 29407532
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
2000 Selective impairment of corticotropin-releasing factor1 (CRF1) receptor-mediated function using CRF coupled to saporin. Endocrinology 18 10650928