corticotropin releasing hormone receptors


Summary: Cell surface proteins that bind corticotropin-releasing hormone with high affinity and trigger intracellular changes which influence the behavior of cells. The corticotropin releasing-hormone receptors on anterior pituitary cells mediate the stimulation of corticotropin release by hypothalamic corticotropin releasing factor. The physiological consequence of activating corticotropin-releasing hormone receptors on central neurons is not well understood.

Top Publications

  1. Gao L, Lu C, Xu C, Tao Y, Cong B, Ni X. Differential regulation of prostaglandin production mediated by corticotropin-releasing hormone receptor type 1 and type 2 in cultured human placental trophoblasts. Endocrinology. 2008;149:2866-76 pubmed publisher
  2. Markovic D, Vatish M, Gu M, Slater D, Newton R, Lehnert H, et al. The onset of labor alters corticotropin-releasing hormone type 1 receptor variant expression in human myometrium: putative role of interleukin-1beta. Endocrinology. 2007;148:3205-13 pubmed
  3. Trimble N, Johnson A, Foster A, Greenwood Van Meerveld B. Corticotropin-releasing factor receptor 1-deficient mice show decreased anxiety and colonic sensitivity. Neurogastroenterol Motil. 2007;19:754-60 pubmed
    ..This study provides pharmacological and genetic evidence for the importance of CRF(1)R in colonic sensitivity and suggests a link between stress and visceral perception. ..
  4. Bradley R, Binder E, Epstein M, Tang Y, Nair H, Liu W, et al. Influence of child abuse on adult depression: moderation by the corticotropin-releasing hormone receptor gene. Arch Gen Psychiatry. 2008;65:190-200 pubmed publisher
  5. Feng P, Liu X, Vurbic D, Fan H, Wang S. Neonatal REM sleep is regulated by corticotropin releasing factor. Behav Brain Res. 2007;182:95-102 pubmed
    ..Our data revealed that blockage of CRF R1 receptors deprives neonatal REM sleep. The mechanism for CRF in enhancing REM sleep may be associated with but not be similar to the cholinergic mechanism. ..
  6. Oakley R, Olivares Reyes J, Hudson C, Flores Vega F, Dautzenberg F, Hauger R. Carboxyl-terminal and intracellular loop sites for CRF1 receptor phosphorylation and beta-arrestin-2 recruitment: a mechanism regulating stress and anxiety responses. Am J Physiol Regul Integr Comp Physiol. 2007;293:R209-22 pubmed
    ..Deficient beta-arrestin-2-CRF(1) receptor interactions could contribute to the pathophysiology of affective disorders by inducing excessive CRF(1) receptor signaling. ..
  7. Rivier J, Gulyas J, Kunitake K, DiGruccio M, Cantle J, Perrin M, et al. Stressin1-A, a potent corticotropin releasing factor receptor 1 (CRF1)-selective peptide agonist. J Med Chem. 2007;50:1668-74 pubmed
    ..Stressin1-A, injected intraperitoneally in rats, induced fecal pellet output (a CRF1 receptor-mediated response) and did not influence gastric emptying and blood pressure (CRF2 receptor-mediated responses). ..
  8. Liu Z, Zhu F, Wang G, Xiao Z, Tang J, Liu W, et al. Association study of corticotropin-releasing hormone receptor1 gene polymorphisms and antidepressant response in major depressive disorders. Neurosci Lett. 2007;414:155-8 pubmed
    ..The results support the idea that the CRHR1 gene is likely to be involved in the antidepressant response in MDD. ..
  9. George O, Ghozland S, Azar M, Cottone P, Zorrilla E, Parsons L, et al. CRF-CRF1 system activation mediates withdrawal-induced increases in nicotine self-administration in nicotine-dependent rats. Proc Natl Acad Sci U S A. 2007;104:17198-203 pubmed
    ..Overactivation of the CRF-CRF(1) system may contribute to nicotine dependence and may represent a prominent target for investigating the vulnerability to tobacco addiction. ..

More Information


  1. Polanczyk G, Caspi A, Williams B, Price T, Danese A, Sugden K, et al. Protective effect of CRHR1 gene variants on the development of adult depression following childhood maltreatment: replication and extension. Arch Gen Psychiatry. 2009;66:978-85 pubmed publisher
    ..This suggests the hypothesis that CRHR1's protective effect may relate to its function in the consolidation of memories of emotionally arousing experiences. ..
  2. Jin D, He P, You X, Zhu X, Dai L, He Q, et al. Expression of corticotropin-releasing hormone receptor type 1 and type 2 in human pregnant myometrium. Reprod Sci. 2007;14:568-77 pubmed
    ..A heterogeneous distribution of CRH-R1 variants in term labor and nonlabor myometrium might be related to the effects of CRH on contractile phenotype of myometrium at the term. ..
  3. Sandi C, Cordero M, Ugolini A, Varea E, Caberlotto L, Large C. Chronic stress-induced alterations in amygdala responsiveness and behavior--modulation by trait anxiety and corticotropin-releasing factor systems. Eur J Neurosci. 2008;28:1836-48 pubmed publisher
    ..Furthermore, they show that CRFR1 antagonists can prevent changes induced by chronic stress, in particular in those animals that are highly anxious. ..
  4. Lu A, Steiner M, Whittle N, Vogl A, Walser S, Ableitner M, et al. Conditional mouse mutants highlight mechanisms of corticotropin-releasing hormone effects on stress-coping behavior. Mol Psychiatry. 2008;13:1028-42 pubmed publisher
    ..Thus, these transgenic mouse lines may serve as animal models for stress-elicited pathologies and treatments that target the central CRH system. ..
  5. Farrokhi C, Tovote P, Blanchard R, Blanchard D, Litvin Y, Spiess J. Cortagine: behavioral and autonomic function of the selective CRF receptor subtype 1 agonist. CNS Drug Rev. 2007;13:423-43 pubmed
    ..Finally, we also discuss preliminary findings of autonomic activation obtained by central injection of cortagine that support CRF1 involvement in the modulation of heart rate and heart rate variability. ..
  6. Ji G, Neugebauer V. Differential effects of CRF1 and CRF2 receptor antagonists on pain-related sensitization of neurons in the central nucleus of the amygdala. J Neurophysiol. 2007;97:3893-904 pubmed
    ..These data suggest that CRF1 receptors in the amygdala contribute to pain-related sensitization, whereas the normally inhibitory function of CRF2 receptors is lost in the arthritis pain model. ..
  7. Lee Y, Fitz S, Johnson P, Shekhar A. Repeated stimulation of CRF receptors in the BNST of rats selectively induces social but not panic-like anxiety. Neuropsychopharmacology. 2008;33:2586-94 pubmed publisher
    ..Thus, BNST priming appears to selectively model the pathophysiology of subjects with anxiety syndromes like social anxiety, which are not lactate sensitive. ..
  8. Tyrka A, Price L, Gelernter J, Schepker C, Anderson G, Carpenter L. Interaction of childhood maltreatment with the corticotropin-releasing hormone receptor gene: effects on hypothalamic-pituitary-adrenal axis reactivity. Biol Psychiatry. 2009;66:681-5 pubmed publisher
    ..Excessive HPA axis activation could represent a mechanism of interactions of risk genes with stress in the development of mood and anxiety disorders. ..
  9. Tezval H, Jurk S, Atschekzei F, Serth J, Kuczyk M, Merseburger A. The involvement of altered corticotropin releasing factor receptor 2 expression in prostate cancer due to alteration of anti-angiogenic signaling pathways. Prostate. 2009;69:443-8 pubmed publisher
  10. Hodgson R, Higgins G, Guthrie D, Lu S, Pond A, Mullins D, et al. Comparison of the V1b antagonist, SSR149415, and the CRF1 antagonist, CP-154,526, in rodent models of anxiety and depression. Pharmacol Biochem Behav. 2007;86:431-40 pubmed
    ..This work demonstrates the different profiles of V1b and CRF1 receptor antagonists and supports both approaches in the treatment of affective disorders. ..
  11. Reyes B, Valentino R, Van Bockstaele E. Stress-induced intracellular trafficking of corticotropin-releasing factor receptors in rat locus coeruleus neurons. Endocrinology. 2008;149:122-30 pubmed
  12. Kirby L, Freeman Daniels E, Lemos J, Nunan J, Lamy C, Akanwa A, et al. Corticotropin-releasing factor increases GABA synaptic activity and induces inward current in 5-hydroxytryptamine dorsal raphe neurons. J Neurosci. 2008;28:12927-37 pubmed publisher
    ..These results regarding the cellular mechanisms underlying the complex interaction between CRF, 5-HT, and GABA systems could contribute to the development of novel treatments for stress-related psychiatric disorders. ..
  13. Papiol S, Arias B, Gasto C, Gutierrez B, Catalan R, Fañanás L. Genetic variability at HPA axis in major depression and clinical response to antidepressant treatment. J Affect Disord. 2007;104:83-90 pubmed
  14. Binneman B, Feltner D, Kolluri S, Shi Y, Qiu R, Stiger T. A 6-week randomized, placebo-controlled trial of CP-316,311 (a selective CRH1 antagonist) in the treatment of major depression. Am J Psychiatry. 2008;165:617-20 pubmed publisher
    ..Given these results, futility was declared for CP-316,311 and the trial was terminated. Although CP-316,311 was safe and well tolerated in this study population, it failed to demonstrate efficacy in the treatment of major depression. ..
  15. Boorse G, Denver R. Widespread tissue distribution and diverse functions of corticotropin-releasing factor and related peptides. Gen Comp Endocrinol. 2006;146:9-18 pubmed
    ..Thus, CRF peptides may play diverse roles in physiology and development, and these functions likely arose early in vertebrate evolution. ..
  16. Gammie S, Stevenson S. Intermale aggression in corticotropin-releasing factor receptor 1 deficient mice. Behav Brain Res. 2006;171:63-9 pubmed
    ..Taken together, the results suggest that the activation CRFR1 is not necessary for the normal production of isolation-induced intermale aggression. ..
  17. Steckler T, Dautzenberg F. Corticotropin-releasing factor receptor antagonists in affective disorders and drug dependence-- an update. CNS Neurol Disord Drug Targets. 2006;5:147-65 pubmed
    ..However, the CRF(2) receptor may be important for motivational types of behavior essential for survival, such as feeding and defense and impacts on cardiovascular function. ..
  18. Nazarloo H, Buttrick P, Saadat H, Dunn A. The roles of corticotropin-releasing factor-related peptides and their receptors in the cardiovascular system. Curr Protein Pept Sci. 2006;7:229-39 pubmed
    ..This review highlights the role of cardiovascular CRF and related peptides and its relevance in mediating the adaptive response of the cardiovascular system to stressful conditions. ..
  19. Slominski A, Zbytek B, Zmijewski M, Slominski R, Kauser S, Wortsman J, et al. Corticotropin releasing hormone and the skin. Front Biosci. 2006;11:2230-48 pubmed
    ..The accumulated evidence indicates that cutaneous CRH is also a component of a local structure organized similarly to the hypothalamo-pituitary-adrenal axis. ..
  20. Slominski A, Zbytek B, Pisarchik A, Slominski R, Zmijewski M, Wortsman J. CRH functions as a growth factor/cytokine in the skin. J Cell Physiol. 2006;206:780-91 pubmed
    ..In conclusion, CRH and related peptides can couple CRH-R1 to any of diverse signal transduction pathways; they also regulate cell viability and proliferation in cell type and growth condition-dependent manners. ..
  21. Fekete E, Zorrilla E. Physiology, pharmacology, and therapeutic relevance of urocortins in mammals: ancient CRF paralogs. Front Neuroendocrinol. 2007;28:1-27 pubmed
    ..Further understanding the unique functions of urocortin 1, urocortin 2, and urocortin 3 action may uncover other therapeutic opportunities. ..
  22. Markovic D, Papadopoulou N, Teli T, Randeva H, Levine M, Hillhouse E, et al. Differential responses of corticotropin-releasing hormone receptor type 1 variants to protein kinase C phosphorylation. J Pharmacol Exp Ther. 2006;319:1032-42 pubmed
    ..Our findings indicate that CRH-R1alpha and -R1beta exhibit differential responses to PKC-induced phosphorylation, and this might represent an important mechanism for functional regulation of CRH signaling in target cells. ..
  23. You X, Yang R, Tang X, Gao L, Ni X. Corticotropin-releasing hormone stimulates estrogen biosynthesis in cultured human placental trophoblasts. Biol Reprod. 2006;74:1067-72 pubmed
    ..These results suggest that, in the placenta, endogenously produced CRH exhibits a tonic stimulatory effect on estrogen production. ..
  24. Hillhouse E, Grammatopoulos D. The molecular mechanisms underlying the regulation of the biological activity of corticotropin-releasing hormone receptors: implications for physiology and pathophysiology. Endocr Rev. 2006;27:260-86 pubmed
    ..The type of activating agonist, receptor, and target cell appears to play a major role in determining the overall signaling and biological responses in health and disease. ..
  25. Grammatopoulos D. The role of CRH receptors and their agonists in myometrial contractility and quiescence during pregnancy and labour. Front Biosci. 2007;12:561-71 pubmed
    ..This review will provide the current concepts about the role of CRH and UCNs and their myometrial receptors during pregnancy, labor and delivery. ..
  26. Hauger R, Risbrough V, Brauns O, Dautzenberg F. Corticotropin releasing factor (CRF) receptor signaling in the central nervous system: new molecular targets. CNS Neurol Disord Drug Targets. 2006;5:453-79 pubmed
    ..If it is confirmed that the CRF(2) receptor contributes importantly to anxiety and depression, the development of small molecule CRF(2) receptor antagonists would be therapeutically useful. ..
  27. Reyes B, Fox K, Valentino R, Van Bockstaele E. Agonist-induced internalization of corticotropin-releasing factor receptors in noradrenergic neurons of the rat locus coeruleus. Eur J Neurosci. 2006;23:2991-8 pubmed
    ..This process may be a pivotal target by which stressors or pharmacological agents regulate the sensitivity of the LC-NE system to CRF and subsequent stressors. ..
  28. Graziani G, Tentori L, Muzi A, Vergati M, Tringali G, Pozzoli G, et al. Evidence that corticotropin-releasing hormone inhibits cell growth of human breast cancer cells via the activation of CRH-R1 receptor subtype. Mol Cell Endocrinol. 2007;264:44-9 pubmed
  29. Holmes K, Babwah A, Dale L, Poulter M, Ferguson S. Differential regulation of corticotropin releasing factor 1alpha receptor endocytosis and trafficking by beta-arrestins and Rab GTPases. J Neurochem. 2006;96:934-49 pubmed
    ..Taken together, our results suggest that beta-arrestin trafficking differs between HEK293 cells and neurons, and that CRF1alpha receptor resensitization is regulated in an atypical manner by Rab GTPases. ..
  30. Yang R, You X, Tang X, Gao L, Ni X. Corticotropin-releasing hormone inhibits progesterone production in cultured human placental trophoblasts. J Mol Endocrinol. 2006;37:533-40 pubmed
    ..In conclusion, placental CRH exhibits a tonic inhibitory effect on progesterone production in a PKC-dependent fashion. ..
  31. Contarino A, Papaleo F. The corticotropin-releasing factor receptor-1 pathway mediates the negative affective states of opiate withdrawal. Proc Natl Acad Sci U S A. 2005;102:18649-54 pubmed
    ..This study reveals a cardinal role for CRF/CRF1 receptor pathways in the negative affective states of opiate withdrawal and suggests therapeutic strategies for the treatment of opiate addiction. ..
  32. Sahuque L, Kullberg E, McGeehan A, Kinder J, Hicks M, Blanton M, et al. Anxiogenic and aversive effects of corticotropin-releasing factor (CRF) in the bed nucleus of the stria terminalis in the rat: role of CRF receptor subtypes. Psychopharmacology (Berl). 2006;186:122-32 pubmed
    ..CRF1 receptors in the BNST mediate the anxiogenic-like effects of CRF in this region, whereas both CRF1 and CRF2 receptor subtypes mediate the conditioned aversive effects of this peptide within the BNST. ..
  33. Valdez G. Development of CRF1 receptor antagonists as antidepressants and anxiolytics: progress to date. CNS Drugs. 2006;20:887-96 pubmed
    ..Further development of these compounds is warranted. ..
  34. Smedh U, Scott K, Moran T. Fourth ventricular CART peptide induces c-fos in the area postrema and nucleus of the solitary tract via a CRF-receptor dependent mechanism. Neurosci Lett. 2015;609:124-8 pubmed publisher
    ..After CARTp and αCRF in combination, there was a tendency towards an increased c-fos response in the ARC. We conclude that CARTp activates cells of the area postrema and NTS via a downstream, CRF-dependent mechanism. ..
  35. Carroll B. Child abuse and adult major depression: no evidence of protective gene. Arch Gen Psychiatry. 2008;65:1336-7; author reply 1337-9 pubmed publisher
  36. Stengel A, Goebel M, Wang L, Rivier J, Kobelt P, Monnikes H, et al. Central nesfatin-1 reduces dark-phase food intake and gastric emptying in rats: differential role of corticotropin-releasing factor2 receptor. Endocrinology. 2009;150:4911-9 pubmed publisher
    ..Activation of nesfatin-1 neurons by cholecystokinin at sites regulating food intake may suggest a role in gut peptide satiation effect. ..
  37. Wang B, You Z, Wise R. Reinstatement of cocaine seeking by hypocretin (orexin) in the ventral tegmental area: independence from the local corticotropin-releasing factor network. Biol Psychiatry. 2009;65:857-62 pubmed publisher
    ..While Hcrt and CRF are known to interact in some area of the brain, in the VTA proper they appear to have largely independent actions on the mesolimbic dopamine mechanisms of cocaine seeking. ..
  38. Newson M, Roberts E, Pope G, Lolait S, O Carroll A. The effects of apelin on hypothalamic-pituitary-adrenal axis neuroendocrine function are mediated through corticotrophin-releasing factor- and vasopressin-dependent mechanisms. J Endocrinol. 2009;202:123-9 pubmed publisher
    ..Together, these data confirm that the in vivo effects of apelin on hypothalamic-pituitary-adrenal neuroendocrine function appear to be mediated through both CRF- and AVP-dependent mechanisms. ..
  39. Kuppast B, Fahmy H. Thiazolo[4,5-d]pyrimidines as a privileged scaffold in drug discovery. Eur J Med Chem. 2016;113:198-213 pubmed publisher
  40. Han X, DeBold J, Miczek K. Prevention and reversal of social stress-escalated cocaine self-administration in mice by intra-VTA CRFR1 antagonism. Psychopharmacology (Berl). 2017;234:2813-2821 pubmed publisher
    ..These findings suggest that CRF and CRFR1 exert multiple roles in the response to social stress that are relevant to escalated cocaine self-administration. ..
  41. Zorrilla E, Koob G. Progress in corticotropin-releasing factor-1 antagonist development. Drug Discov Today. 2010;15:371-83 pubmed publisher
    ..The therapeutic utility of CRF(1) antagonists should soon be clearer: several small molecules are currently in Phase II/III clinical trials for depression, anxiety and irritable bowel syndrome. ..
  42. Mokhtarpour M, Elahdadi Salmani M, Lashkarbolouki T, Abrari K, Goudarzi I. Lateral hypothalamus orexinergic system modulates the stress effect on pentylenetetrazol induced seizures through corticotropin releasing hormone receptor type 1. Neuropharmacology. 2016;110:15-24 pubmed publisher
  43. Todorovic C, Radulovic J, Jahn O, Radulovic M, Sherrin T, Hippel C, et al. Differential activation of CRF receptor subtypes removes stress-induced memory deficit and anxiety. Eur J Neurosci. 2007;25:3385-97 pubmed
    ..We propose that the enhanced anxiety is the component of the stress response responsible for the memory deficit. ..
  44. Pentkowski N, Litvin Y, Blanchard D, Vasconcellos A, King L, Blanchard R. Effects of acidic-astressin and ovine-CRF microinfusions into the ventral hippocampus on defensive behaviors in rats. Horm Behav. 2009;56:35-43 pubmed publisher
    ..These results suggest a specific role for ventral hippocampal CRF receptors in modulating anxiety-like behaviors in several ethologically relevant animal models of defense. ..
  45. Jokinen J, Boström A, Chatzittofis A, Ciuculete D, Öberg K, Flanagan J, et al. Methylation of HPA axis related genes in men with hypersexual disorder. Psychoneuroendocrinology. 2017;80:67-73 pubmed publisher
    ..CRH is an important integrator of neuroendocrine stress responses in the brain, with a key role in the addiction processes. Our results show epigenetic changes in the CRH gene related to hypersexual disorder in men. ..
  46. Ohmura Y, Yoshioka M. The roles of corticotropin releasing factor (CRF) in responses to emotional stress: is CRF release a cause or result of fear/anxiety?. CNS Neurol Disord Drug Targets. 2009;8:459-69 pubmed
    ..In other words, CRF could be responsible for stress responses to cope with dangerous situations but not for fear/anxiety itself. CRF as a potential target of drug development for treatment of stress-related disorders is also discussed. ..
  47. Nagy J. Recent patents on pharmacotherapy for alcoholism. Recent Pat CNS Drug Discov. 2006;1:175-206 pubmed
    ..The aim of this review is to summarize the patent background of these potential candidates clustering them according to their mechanism of effects. ..
  48. Fu Y, Neugebauer V. Differential mechanisms of CRF1 and CRF2 receptor functions in the amygdala in pain-related synaptic facilitation and behavior. J Neurosci. 2008;28:3861-76 pubmed publisher
    ..Presynaptic CRF2 receptor-mediated inhibition does not reach behavioral significance. ..
  49. Rademaker M, Richards A. Urocortins: Actions in health and heart failure. Clin Chim Acta. 2017;474:76-87 pubmed publisher
    ..All three Ucns exert salutary hemodynamic, neurohormonal and renal effects in experimental heart failure and recent clinical trials have demonstrated hemodynamic benefits of Ucn2 administration. ..
  50. Wasserman D, Sokolowski M, Rozanov V, Wasserman J. The CRHR1 gene: a marker for suicidality in depressed males exposed to low stress. Genes Brain Behav. 2008;7:14-9 pubmed
    ..002), among whom most males were depressed (P = 0.001). The identified allele may represent a part of the genetic susceptibility for suicidality by increasing HPA axis activity upon exposure to low levels of stress. ..
  51. Sheng H, Sun T, Cong B, He P, Zhang Y, Yan J, et al. Corticotropin-releasing hormone stimulates SGK-1 kinase expression in cultured hippocampal neurons via CRH-R1. Am J Physiol Endocrinol Metab. 2008;295:E938-46 pubmed publisher
    ..Our results suggest that CRH act on CRH-R1 to stimulate SGK-1 mRNA and protein expression in cultured hippocampal neurons via a mechanism that is involved in AC/PKA signaling pathways. ..
  52. Stahl S, Wise D. The potential role of a corticotropin-releasing factor receptor-1 antagonist in psychiatric disorders. CNS Spectr. 2008;13:467-83 pubmed
  53. Roy B, Shelton R, Dwivedi Y. DNA methylation and expression of stress related genes in PBMC of MDD patients with and without serious suicidal ideation. J Psychiatr Res. 2017;89:115-124 pubmed publisher
    ..Thus, our findings underline the importance of epigenetic modifications of stress-associated genes in depression and, possibly, suicidal behavior, which, in future, needs to be confirmed in a larger patient population. ..