corticotropin-releasing hormone receptor

The hypothalamic-pituitary-adrenal (HPA) axis is a central neuroendocrine system that modulates the body's response to stress. It governs the release of hormones that prepare the body for immediate action—the “fight or flight” response—and subsequently restore physiological balance. At the core of this system is the release of corticotropin-releasing hormone (CRH) from the hypothalamus, which binds to corticotropin-releasing hormone receptors (CRHRs) in the anterior pituitary gland. This interaction stimulates the secretion of adrenocorticotropic hormone (ACTH), which acts on the adrenal glands to release cortisol.{{cite journal | title = Hypothalamic-Pituitary-Adrenal (HPA) Axis | date = April 12, 2024 | url = https://my.clevelandclinic.org/health/body/hypothalamic-pituitary-adrenal-hpa-axis | access-date = March 8, 2025 | website = Cleveland Clinic }}

Cortisol increases blood glucose levels, improves cardiovascular output, and suppresses non-essential functions such as digestion and reproduction, enabling the body to respond effectively to stress. However, chronic elevation of cortisol may contribute to immune suppression, obesity, and cardiovascular disease.

CRH binds to two receptor subtypes—CRHR1 and CRHR2—which are G protein-coupled receptors (GPCRs) that activate different intracellular signaling pathways depending on ligand, tissue, and context. CRHR1 generally couples with Gα_s proteins, triggering adenylyl cyclase, cAMP production, and activation of protein kinase A (PKA).{{Cite journal | vauthors = Inda C, Armando NG, Claro PA, Silberstein S | title = Endocrinology and the brain: corticotropin-releasing hormone signaling | journal = Endocrine Connections | volume = 6 | issue = 6 | pages = R99–R120 | date = August 2017 | pmid = 28710078 | pmc = 5551434 | doi = 10.1530/EC-17-0111 | url = https://ec.bioscientifica.com/view/journals/ec/6/6/R99.xml | issn = 2049-3614 }}

CRHR2 also couples with G proteins but preferentially activates pathways involving phospholipase C, leading to hydrolysis of PIP₂ into IP3 and DAG, which mobilize calcium and activate protein kinase C (PKC), respectively.{{cite journal | title = GPCR {{!}} Learn Science at Scitable|url=https://www.nature.com/scitable/topicpage/gpcr-14047471/|access-date=2025-03-09|website=www.nature.com|language=en}}

The HPA axis uses negative feedback to regulate hormone levels. Elevated cortisol suppresses CRH and ACTH production, ensuring return to homeostasis.{{Cite journal | vauthors = Henley C | title = HPA Axis | journal = Foundations of Neuroscience | date = 2021-01-01 | url = https://openbooks.lib.msu.edu/neuroscience/chapter/hpa-axis/#:~:text=Negative%20Feedback,shut%20off%20its%20own%20production | language = en }} Disruption of this loop can lead to sustained cortisol elevation, contributing to psychiatric disorders and metabolic diseases.{{cite journal | vauthors = Raise-Abdullahi P, Meamar M, Vafaei AA, Alizadeh M, Dadkhah M, Shafia S, Ghalandari-Shamami M, Naderian R, Samaei S, Rashidy-Pour A | title = Hypothalamus and Post-Traumatic Stress Disorder: A Review | journal = Brain Sciences | volume = 13 | issue = 7 | date = June 23, 2023 | page = 1010 | pmid = 37508942 | pmc = 10377115 | doi = 10.3390/brainsci13071010 | doi-access = free }}

CRHR1 is highly expressed in stress-responsive brain regions such as the hypothalamus, amygdala, and hippocampus. Upon activation by CRH, it triggers ACTH release through hypothalamic-pituitary-adrenal (HPA) axis activation and initiates the physiological stress response.{{Cite journal | vauthors = Chinnathambi S, Chidambaram H | title = G-Protein Coupled Receptors and Tau-different Roles in Alzheimer's Disease | journal = Neuroscience | volume = 438 | pages = 198–214 | date = 2020-07-01 | pmid = 32335218 | doi = 10.1016/j.neuroscience.2020.04.019 | url = https://www.sciencedirect.com/science/article/abs/pii/S0306452220302414 | issn = 0306-4522 | url-access = subscription }} CRHR1 activation enhances neuronal excitability in the hippocampus by modulating potassium channels (K_V1 subfamily), increasing population spike amplitudes through presynaptic mechanisms.{{Cite journal | vauthors = Refojo D, Schweizer M, Kuehne C, Ehrenberg S, Thoeringer C, Wolf AM, von Wolff G, Avrabos C, Touma C, Engblom D, Schütz G, Nave KA, Eder M, Wotjak CT, Sillaber I, Holsboer F, Wurst W, Deussing JM | title = Glutamatergic and dopaminergic neurons mediate anxiogenic and anxiolytic effects of CRHR1 | journal = Science | location = New York, N.Y. | volume = 333 | issue = 6051 | pages = 1871–1874 | date = 2011-09-30 | pmid = 21960631 | doi = 10.1126/science.1202107 | bibcode = 2011Sci...333.1903R }}

In the amygdala, CRHR1 enhances fear and anxiety through G_sα-coupled signaling pathways that increase cAMP production and CREB phosphorylation.{{Cite journal | vauthors = Hubbard DT, Nakashima BR, Lee I, Takahashi LK | title = Activation of basolateral amygdala corticotropin-releasing factor 1 receptors modulates the consolidation of contextual fear | journal = Neuroscience | volume = 150 | issue = 4 | pages = 818–828 | date = 2007-12-19 | pmid = 17988803 | pmc = 2174904 | doi = 10.1016/j.neuroscience.2007.10.001 }} Hippocampal CRHR1 activation impairs memory and learning by reducing long-term potentiation through calcineurin-mediated suppression of potassium currents (I_A and I_K).{{Cite journal | vauthors = Blank T, Nijholt I, Eckart K, Spiess J | title = Priming of long-term potentiation in mouse hippocampus by corticotropin-releasing factor and acute stress: implications for hippocampus-dependent learning | journal = The Journal of Neuroscience | volume = 22 | issue = 9 | pages = 3776–3787 | date = 2002-05-01 | pmid = 11978853 | pmc = 6758446 | doi = 10.1523/JNEUROSCI.22-09-03788.2002 }}

Dysregulation of CRHR1 contributes to anxiety, depression, PTSD, and cognitive impairment. Chronic CRHR1 activation leads to HPA axis hyperactivity and reduced hippocampal neurogenesis.{{Cite journal | vauthors = Goparaju P, Postolache TT, del Bosque-Plata L, Gragnoli C, Perrelli M | title = Stress and the CRH System, Norepinephrine, Depression, and Type 2 Diabetes | journal = Biomedicines | volume = 12 | issue = 6 | pages = 1187 | date = June 2024 | pmid = 38927393 | pmc = 11200886 | doi = 10.3390/biomedicines12061187 | doi-access = free }} Genetic studies show specific CRHR1 variants (rs12938031, rs4792887) increase PTSD risk after trauma exposure through impaired cortisol feedback.{{Cite journal | vauthors = Acierno R, Ruggiero KJ, Koenen KC, Kilpatrick DG, Galea S, Gelernter J, Williamson V, McMichael O, Vladimirov VI, Amstadter AB, White S | title = Association of CRHR1 variants and posttraumatic stress symptoms in hurricane exposed adults | journal = Journal of Anxiety Disorders | volume = 27 | issue = 7 | pages = 678–683 | date = 2013-10-01 | pmid = 24077033 | pmc = 4182958 | doi = 10.1016/j.janxdis.2013.08.003 | issn = 0887-6185 }} Preclinical models demonstrate CRHR1 antagonists reverse stress-induced dendritic atrophy in prefrontal cortex pyramidal neurons.{{Cite journal | vauthors = Sagar GD, Gereben B, Callebaut I, Mornon JP, Zeöld A, Curcio-Morelli C, John W, Luongo C, Michelle A, Larsen PR, Stephen A, Antonio C | title = Central Nervous System-Specific Knockout of Steroidogenic Factor 1 | journal = Molecular Endocrinology | location = Baltimore, Md. | volume = 22 | issue = 6 | pages = 1382–1393 | date = 2008-06-01 | pmid = 18356288 | pmc = 2422836 | doi = 10.1210/me.2007-0490 }}

CRHR2 expression is more restricted but includes the ventromedial hypothalamus, bed nucleus of stria terminalis, and peripheral tissues. It serves to attenuate the stress response through urocortin 3 binding, which activates G_q-coupled pathways that suppress CRH release and enhance negative feedback.{{Cite journal | vauthors = Inda C, Bonfiglio JJ, dos Santos Claro PA, Senin SA, Armando NG, Deussing JM, Silberstein S | title = cAMP-dependent cell differentiation triggered by activated CRHR1 in hippocampal neuronal cells | journal = The American Journal of Case Reports | volume = 18 | issue = 1 | pages = 537–540 | date = 2017-05-15 | pmid = 28507284 | pmc = 5431483 | doi = 10.1038/s41598-017-02134-z | bibcode = 2017NatSR...7.1944I }} CRHR2 activation increases brain-derived neurotrophic factor (BDNF) expression in the ventral tegmental area, promoting stress resilience.

CRHR2 dysfunction impairs HPA axis recovery, contributing to prolonged stress responses and emotional dysregulation. Knockout models show 40% increased anxiety-like behaviors in elevated plus maze tests and delayed cortisol normalization after restraint stress. Human studies link CRHR2 polymorphisms to altered startle response habituation and impaired fear extinction in PTSD patients.{{Cite journal | vauthors = Kishimoto T, Radulovic J, Radulovic M, Lin CR, Schrick C, Hooshmand F, Hermanson O, Rosenfeld MG, Spiess J | title = Deletion of crhr2 reveals an anxiolytic role for corticotropin-releasing hormone receptor-2 | journal = Nature Genetics | volume = 24 | issue = 4 | pages = 415–419 | date = 2000-04-01 | pmid = 10742109 | doi = 10.1038/74271 }} The receptor's peripheral effects include modulation of cardiovascular tone through ERK1/2-dependent pathways in vascular smooth muscle cells.{{cite journal | vauthors = Parra-Mercado GK, Fuentes-Gonzalez AM, Hernandez-Aranda J, Diaz-Coranguez M, Dautzenberg FM, Catt KJ, Hauger RL, Olivares-Reyes JA | title = CRF1 Receptor Signaling via the ERK1/2-MAP and Akt Kinase Cascades: Roles of Src, EGF Receptor, and PI3-Kinase Mechanisms | journal = Frontiers in Endocrinology | volume = 10 | issue = | pages = 869 | date = 2019 | pmid = 31920979 | pmc = 6921279 | doi = 10.3389/fendo.2019.00869 | doi-access = free }}{{cite journal | vauthors = Walczewska J, Dzieza-Grudnik A, Siga O, Grodzicki T | title = The role of urocortins in the cardiovascular system | journal = Journal of Physiology and Pharmacology | volume = 65 | issue = 6 | pages = 753–766 | date = December 2014 | pmid = 25554979 | doi = | url = }}

Both CRHR1 and CRHR2 activate intracellular cascades involving cAMP/PKA or IP3/DAG signaling. These influence gene expression, including activation of CREB, a transcription factor that upregulates genes related to plasticity, stress response, and immunity. Sustained CRHR activation can create a feedback loop of increased CRH expression, contributing to receptor desensitization and maladaptive stress responses.

Polymorphisms in CRHR1 and CRHR2 genes influence receptor function and stress vulnerability. CRHR1 SNPs have been linked to increased risk of anxiety and depression, especially in individuals exposed to early-life stress.{{Cite journal | vauthors = Smoller JW | title = The Genetics of Stress-Related Disorders: PTSD, Depression, and Anxiety Disorders | journal = Neuropsychopharmacology | volume = 41 | issue = 1 | pages = 297–319 | date = August 31, 2015 | pmid = 26321314 | pmc = 4677147 | doi = 10.1038/npp.2015.266 | language = en | issn = 1740-634X }}

Variants in CRHR2 are associated with better stress recovery and reduced PTSD risk, likely due to improved feedback regulation of cortisol.{{cite journal | vauthors = Wolf EJ, Mitchell KS, Logue MW, Baldwin CT, Reardon AF, Humphries DE, Miller MW | title = The Corticotropin Releasing Hormone Receptor 2 (CRHR-2) Gene is Associated with Decreased Risk and Severity of Posttraumatic Stress Disorder in Women | journal = Depression and Anxiety | volume = 30 | issue = 12 | pages = 1161–1169 | date = December 1, 2014 | pmid = 24123648 | pmc = 3855198 | doi = 10.1002/da.22176 }}

Antagonists targeting CRHR1 have shown promise in reducing anxiety, depression, and PTSD symptoms by limiting cortisol release and dampening stress-related signaling. For example, Verucerfont (GSK561679), a selective CRHR1 antagonist, has been evaluated of treating PTSD symptoms in a Phase II randomized controlled trial involving women with chronic PTSD.{{Cite journal | vauthors = Rothbaum BO, Binder EB, Duncan E, Harvey PD, Jovanovic T, Kelley ME, Kinkead B, Kutner M, Iosifescu DV, Mathew SJ, Neylan TC, Kilts CD, Nemeroff CB, Mayberg HS, Dunlop BW | title = Evaluation of a corticotropin releasing hormone type 1 receptor antagonist in women with posttraumatic stress disorder | journal = Trials | volume = 15 | issue = 1 | pages = 240 | date = 2014-06-21 | pmid = 24950747 | pmc = 4082482 | doi = 10.1186/1745-6215-15-240 | doi-access = free }} The CRHR1 antagonist antalarmin has been shown in animal studies to protect against stress-induced colonic injury by reducing NF-κB-mediated inflammation and stabilizing gut microbiota.{{Cite journal | vauthors = Larauche M, Kiank C, Tache Y | title = Corticotropin releasing factor signaling in colon and ileum: regulation by stress and pathophysiological implications | journal = Journal of Physiology and Pharmacology | volume = 60 | issue = Suppl 7 | pages = 33–46 | date = December 2009 | pmid = 20388953 }}

NBI30775 (R121919), which reversed synaptic loss in hippocampal CA1/CA3 regions and rescued trauma-induced memory deficits in aged mice.{{Cite journal | vauthors = Wang X, Li G, Liu Y, Liu Y, Wang Y, Wang Y, Li X, Li Y, Liu J | title = CRHR1 antagonist reverses synaptic loss and cognitive deficits induced by chronic stress in aged mice | journal = Frontiers in Aging Neuroscience | volume = 12 | pages = 245 | date = 2020-04-28 | pmid = 32410909 | pmc = 7201786 | doi = 10.3389/fnagi.2020.00245 | doi-access = free }} Mechanistically, CRHR1 antagonists suppress Gαs-cAMP-PKA signaling cascades, normalizing HPA axis hyperactivity and dendritic atrophy in prefrontal cortex neurons.{{Cite journal | vauthors = Qiu L, Zhang H, Zhou Z, Ju L, Yang J, Sun J | title = CRHR1 antagonist alleviates LPS-induced depression-like behaviour in mice | journal = BMC Psychiatry | volume = 23 | issue = 1 | pages = 17 | date = 2023-01-09 | pmid = 36624454 | pmc = 9830857 | doi = 10.1186/s12888-023-04519-z | doi-access = free }}

Drugs targeting CRHR2 aim to enhance feedback mechanisms and restore balance in the HPA axis. The orally bioavailable CRHR2 antagonist RQ-00490721 attenuated pressure overload-induced cardiac dysfunction in mice by suppressing CREB/AKT phosphorylation pathways, highlighting its potential for heart failure treatment.{{Cite journal | vauthors = Yamamoto T, Saito Y, Nakayama K, Sato T, Nakamura T, Yamada T, Oikawa R, Takahashi N, Itoh H | title = A novel, orally available corticotropin-releasing hormone receptor type 2-selective antagonist, RQ-00490721, attenuates pressure overload-induced cardiac dysfunction in mice | journal = European Journal of Pharmacology | volume = 911 | pages = 174487 | date = 2021-11-15 | issue = 7 | pmid = 34517258 | doi = 10.1016/j.ejphar.2021.174487 | pmc = 9372922 }} CRHR2 activation via urocortin 2 promotes stress resilience by increasing BDNF expression in the ventral tegmental area and facilitating fear extinction.{{Cite journal | vauthors = Kormos V, Gaszner B, Kovács KJ | title = Role of CRH in neural plasticity and stress-induced pathology | journal = Frontiers in Endocrinology | volume = 7 | pages = 123 | date = 2016-09-13 | pmid = 27679536 | pmc = 5027273 | doi = 10.3389/fendo.2016.00123 | doi-access = free }}

Genetic studies reveal that CRHR2 knockout models exhibit increased anxiety-like behaviors and impaired cortisol normalization post-stress.{{Cite journal | vauthors = Bale TL, Contarino A, Smith GW, Chan R, Gold LH, Sawchenko PE, Koob GF, Vale WW, Lee KF | title = Mice deficient for corticotropin-releasing hormone receptor-2 display anxiety-like behaviour and are hypersensitive to stress | journal = Nature Genetics | volume = 24 | issue = 4 | pages = 410–414 | date = April 2000 | pmid = 10742109 | doi = 10.1038/74271 }} Emerging modulators aim to exploit CRHR2's role in peripheral tissues-for example, its ERK1/2-dependent regulation of vascular smooth muscle tone-to address stress-related cardiovascular comorbidities.{{Cite journal | vauthors = Kageyama K, Suda T | title = Regulatory mechanisms underlying corticotropin-releasing factor receptor expression in the hypothalamus | journal = Endocrine Journal | volume = 66 | issue = 3 | pages = 227–234 | date = 2019-03-28 | pmid = 30700619 | doi = 10.1507/endocrj.EJ18-0441 | doi-access = free }}

{{Reflist|2}}

• {{cite journal | title = Corticotropin-Releasing Factor Receptors | url = http://www.iuphar-db.org/GPCR/ChapterMenuForward?chapterID=1321 | journal = IUPHAR Database of Receptors and Ion Channels | publisher = International Union of Basic and Clinical Pharmacology | access-date = 2007-10-25 | archive-date = 2016-03-03 | archive-url = https://web.archive.org/web/20160303173004/http://www.iuphar-db.org/GPCR/ChapterMenuForward?chapterID=1321 | url-status = dead }}
• {{MeshName|Corticotropin-releasing+hormone+receptors}}

{{G protein-coupled receptors}}

{{Neuropeptide receptors}}