id: PW:0000493 rgd_url: https://rgd.mcw.edu/rgdweb/pathway/pathwayRecord.html?processType=view&species=Rat&acc_id=PW:0000493 title: corticotropin-releasing hormone signaling pathway description: Corticotropin-releasing hormone (CRH) and CRH-relate urocortin (UCN) peptides exert a wide range of functions, from setting in motion the stress-responding hypothalamus-pituitary-adrenal (HPA) axis to various actions in central nervous system (CNS) and the periphery. The signaling initiated by these peptides engages two receptor types belonging to the secretin family of G-protein coupled receptors (GPCR). CRH is a main component of the HPA axis; released by the hypothalamus in response to stress, it leads to activation and release of adrenocorticotropin (ACTH) from the pituitary which in turn activates the synthesis and release of glucocorticoids from the adrenal cortex. Glucocorticoid (cortisol in humans) signaling activates the nuclear glucocorticoid receptor which translocates to the nucleus to initiate a gene expression regulatory programme with important anti-inflammatory and metabolic roles. In addition, due to its expression in many tissues, CRH also plays important roles in metabolism, immunity, reproduction and behavior. UCN peptides are expressed in CNS and the periphery with no overlap between them and CRH. Their roles are less well understood but evidence suggests important functions in cardiovascular system and appetite control. Of the two types of receptors, CRH receptor type 1 (CRHR1), is expressed in the brain, pituitary and many other tissues. CRHR2 is also expressed in the brain and periphery; the distribution pattern of the two receptors is distinct. CRH preferentially binds CRHR1, UCN1 can bind either receptor, UCN2 and 3 bind CRHR2. A circulating protein of 37kDa can bind CRH and UCN; while it can block CRH-activated secretion of ACTH from pituitary cultures, its exact role remains to be determined. Both receptors predominantly couple to the Galphas class of heterotrimeric G proteins. Activated Galphas promotes stimulation of adenylyl cyclases and subsequent cAMP production which activated protein kinase A (PKA) signaling. Other classes of G protein such as Galphaq or Galpahai may also be coupled but it is not clear whether genetic background and/or species preferences are involved (not shown). Activated PKA via direct post-translational modification of target proteins in the cytoplasm and also in the nucleus or at the level of regulation of gene transcription via cAMP response element-binding (CREB) protein, impacts on many important cellular pathways and physiological processes. CRH-induced activation of CREB leads to the expression of genes such as the orphan nuclear receptors which in turn, activate the transcription of pro-opiomelanocortin (POMC) gene. POMC is the precursor of ACTH and several other functional peptides. ACTH employs the same intracellular route of PKA activation to prompt the transcription of steroidogenic enzymes and proteins along the PHA axis. CRHR1 is target of G-protein coupled receptor kinases (GRK) 3 and 6; phosphorylation promotes the interaction with beta-arrestin leading to receptor desensitization and internalization. diagram_image: https://rgd.mcw.edu/pathway/PW0000493/corticotropin-releasing%20hormone%20signaling%20pathway/pwmap.png pathway_studio_file: https://rgd.mcw.edu/pathway/PW0000493/corticotropin-releasing%20hormone%20signaling%20pathway/corticotropin-releasing%20hormone%20signaling%20pathway.gpp diagram_pathway_links: - id: PW:0000227 label: G protein mediated signaling pathway via Galphas family - id: PW:0000365 label: melanocortin system pathway - id: PW:0000543 label: protein kinase A (PKA) signaling pathway diagram_gene_links: - id: RGD:2063 label: Adrbk2 - id: RGD:2156 label: Arrb1 - id: RGD:2157 label: Arrb2 - id: RGD:620505 label: Crh - id: RGD:2403 label: Crhbp - id: RGD:61276 label: Crhr1 - id: RGD:70547 label: Crhr2 - id: RGD:2716 label: Gnas - id: RGD:61986 label: Grk6 - id: RGD:3929 label: Ucn - id: RGD:620765 label: Ucn2 - id: RGD:1562213 label: Ucn3 diagram_chemicals: - id: PUBCHEM.COMPOUND:6076 label: cAMP diagram_edges: - source: Adrbk2 relation: negatively_affects target: Crhr1 - source: Arrb1 relation: associated_with target: Crhr1 - source: Arrb2 relation: associated_with target: Crhr1 - source: Crh relation: associated_with target: Crhbp - source: Crh relation: associated_with target: Crhr1 - source: Crhbp relation: associated_with target: Ucn - source: Crhr1 relation: associated_with target: Gnas - source: Crhr1 relation: associated_with target: Ucn - source: Crhr2 relation: associated_with target: Gnas - source: Crhr2 relation: associated_with target: Ucn - source: Crhr2 relation: associated_with target: Ucn2 - source: Crhr2 relation: associated_with target: Ucn3 - source: Grk6 relation: negatively_affects target: Crhr1 - source: Ucn relation: positively_affects target: cardiovascular functions - source: Ucn2 relation: positively_affects target: cardiovascular functions - source: Ucn3 relation: positively_affects target: cardiovascular functions diagram_labels: - cAMP --+> protein kinase A (PKA) signaling pathway - cardiovascular functions - Crh --+> melanocortin system pathway - CRH neurons - G protein mediated signaling pathway via Galphas family --+> cAMP - gene expression - HPA axis - receptor - G protein uncoupling - receptor desensitization - receptor internalization - stress - stress --+> CRH neurons references: - id: RGD:5147387 citation: Hillhouse EW and Grammatopoulos DK, Endocr Rev. 2006 May;27(3):260-86. Epub 2006 Feb 16. - id: RGD:5147673 citation: Hauger RL, etal., CNS Neurol Disord Drug Targets. 2006 Aug;5(4):453-79. - id: RGD:5147736 citation: Aguilera G Exp Gerontol. 2011 Feb-Mar;46(2-3):90-5. Epub 2010 Sep 9. - id: RGD:5147737 citation: Refojo D and Holsboer F, Ann N Y Acad Sci. 2009 Oct;1179:106-19. - id: RGD:5147738 citation: Papadimitriou A and Priftis KN, Neuroimmunomodulation. 2009;16(5):265-71. Epub 2009 Jun 29. - id: RGD:5147739 citation: Yang LZ, etal., Eur J Pharmacol. 2010 Apr 25;632(1-3):1-6. Epub 2010 Feb 2. - id: RGD:5147740 citation: Holmes KD, etal., J Neurochem. 2006 Feb;96(4):934-49. Epub 2006 Jan 12. - id: RGD:5147741 citation: Gallagher JP, etal., Eur J Pharmacol. 2008 Apr 7;583(2-3):215-25. Epub 2008 Feb 1. - id: RGD:5147742 citation: Yao M and Denver RJ, Gen Comp Endocrinol. 2007 Aug-Sep;153(1-3):200-16. Epub 2007 Feb 17. - id: RGD:5147743 citation: Ulrich-Lai YM and Herman JP, Nat Rev Neurosci. 2009 Jun;10(6):397-409.