Corticotropin-releasing hormone (Bos taurus)

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PRKCQPcGMPNOActivated inkeratinocytesthymocytesNUFatty acidoxidationCorticotropin-Releasing Hormone Signaling PathwayGuanylateCYProinflammatory effect in leukocytesCyclaseNUmRNAInhibited inmelanocytespituitary corticotrophspituitary tumor cellsENRegulation of CRHPlacentalvesselvasodilationCYNUAdenylateNUCYENDesensitizationIncreased gap junctionsNeuroprotectionVEGF releasein mast cellsFASL releasein PC12 cellsCYPMRecycling of receptorsApoptosis inMicroglial cellsHippocampal neuronsProstate cancer cellsNUCYDehydroepiandrosterone sulfate and cortisol productionKeratinocytedifferentiationand proliferationCell survivalNUCYNUPMCYNeuronalsurvivalInhibits Cell proliferationCRHBPNR4A1FOSL2JUNBCRHIL18CXCL8PRKAA2RHOAJUPFOSPRKANOS3ACACAPTK2CACNA1HTLR4NCOA2SP1NR4A1FOSL1TRIM28JUNBFOSBS80PT172PRKCIPPRKCDPHSD3BTCF7L2TFAP2ACTNNB1ACTH productionMAPK3T204T202IL2KRT1MAPK9T183Y185NR4A2CRHR2MAPK1Y187CRHY185SP1CYP11A1HSP90AA1IVLCRHR1NR4A1S301S412S386CRHTFAP2ACRHR1RAPGEF3CTNNB1KRT14Enzyme complexTranslocation DeubiquitinationActivationInhibitionAcetylationNegative regulation of gene expressionLEGENDLeads to through unknown mechanismPhosphorylationProtein-protein interactionTransportUbiquitinationDephosphorylationInduced catalysisAuto catalysisSumoylationPositive regulation of gene expressionTGFB1TGFB1RAF1DeacetylationGolgi apparatusEndosomeNucleusMitochondrionDesumoylationMethylationDemethylationPalmitoylationCytoplasmECPlasma membraneMTEndoplasmic reticulumCYPMGONUExtracellularERENProteolytic cleavageRELAPRKCBPPRKCAPGNAQCREB1S133PRKAcAMPGNB5GNB3GNB2GNB1ADRBK2GNA11GNAO1GNASGNAI2GNAI1DAGIP3PIP2MAP2K1BRAFRAP1BCRHR1PLCG2S537PPLCG1PGSK3BS9PARP1PCCASP9PCCASP3PCCASP12PCMAPK8Y185T183MAP3K5PERN1PCYP21A2CYP17A1STARCYP11B1CYP11A1CAMK2AHSD3BGRK6ADRBK2ECE1BIKBAPCGJA1CRHR2ARRB1SULT2A1ADRBK2CRHARRB2RELABCL2PI3KAKT1S473POMCNR4A2FOSCalciumPMCYARRB1ARRB2PMCYECE1CRHCRHR1CRHR2CRHCRHR1T399CRHCyclaseGNAZELK1TBX19FOSG-gammaInhibits Progesterone synthesis in Placental trophoblastspathwayDegradationand dissociationof NFKBsNFKB1NFKB1NFKB1MAPK14T180Y182NR4A1AP-1 complexClathrin and arrestin mediated endocytosisENPMPro-inflammatorycytokine productionCRHCRHBPProtein


Description

Corticotropin-releasing hormone (CRH) is a neuropeptide secreted abundantly in the paraventricular nucleus of the hypothalamus, amygdala, cerebral cortex and cerebellum in the central nervous system It is also expressed in adrenal gland, placenta, testis, spleen, gut, thymus and skin . CRH is the principal mediator of endocrine stress response . CRH also plays a significant role in inflammatory responses , hemodynamic actions , stromal cell decidualization during estrus cycle , implantation of blastocyst , maintenance of pregnancy, onset of labor and neuroprotection . Excess secretion of CRH during severe depression and its association with increased levels of cortisol have been observed . CRH has also been reported to be involved in anxiety disorders , anorexia nervosa . Decrease in cortical CRH content has been observed in Alzheimer's disease and Parkinson's disease .

The actions of CRH are mediated through class II/secretin-like family type of G-protein coupled receptor (GPCR) called the CRH receptors (CRHR) . CRH is a high affinity ligand of CRHR1 and also binds to CRHR2 but with lower affinity . CRH receptors do not have any intrinsic kinase activity and transduce the signal via the heterotrimeric G-proteins . The CRH receptors are rapidly desensitized by G-protein-coupled receptor kinase (GRK) and β-arrestin mechanisms in the presence of high concentrations of CRH . Binding of CRH to CRH receptor induces a conformational change in the receptor by activating it. This further activates Gα-subunit and its subsequent dissociation from the Gβγ dimer. CRH receptors on interaction with Gα-subunit of different G-proteins such as Gαs, Gαi/o, Gαq/11 activate numerous downstream signaling cascades and result in the induction of various cellular responses . The pathways that are activated upon CRH stimulation are: Adenylate cyclase/cAMP/PKA, PLC/PKC, ERK/MAPK, PI3K-AKT and NF-kappa B.

CRH binding to CRHR1 couples G-stimulatory (Gs) protein which in turn activates cAMP-dependent protein kinase (PKA). Activation of PKA leads to the phosphorylation of transcription factors like cAMP response element binding protein (CREB), which in turn increases the expression of pro-opiomelanocortin (POMC) gene and the release of POMC-derived peptides, adrenocorticotropic hormone (ACTH) and β-endorphin. ACTH, in turn, stimulates the secretion of glucocorticoids from adrenal glands and thereby mediates changes associated with stress response . CREB also regulates genes containing the Ca2+/cAMP response element such as FOS . The activation of cAMP by CRH induces the mRNA expression and transcription of orphan nuclear receptors NR4A1 and NR4A2, which in turn transcriptionally activates the expression of POMC . Activation of cAMP/PKA can also induce the expression of enzymes involved in dehydroepiandrosterone sulfate and cortisol production . The biological functions of CRH are also mediated by MAPK family, in particular MAPK1/3 and MAPK14. MAPK1/3 mediates activation of transcription factors NR4A1 and NR4A2 and induction of POMC in corticotrophs . MAPK14 is involved in CRH-induced inhibition of IL-18 expression in human keratinocytes . The CRHR1/PKA/ERK signaling activate the transcription factors - ELK1 , SP1 and TFAP2A. SP1 and TFAP2A up-regulates the expression of ADRBK2, which causes the desensitization of CRHR1 receptors .

The PLC/PKC pathway is activated by coupling of the CRH receptors to the Gαq/11 proteins. This cascade stimulates the formation of IP3 and contributes to the mobilization of intracellular calcium. Calcium is involved in the transcription regulation of FOS as well as NR4A1 and NR4A2 through CAMK2A. PLC/PKC is involved in the activation of AP-1 complex and subsequent transcriptional regulation of genes involved in keratinocyte differentiation and proliferation – KRT1, KRT14 and IVL . This cascade also inhibits the expression of CYP11A1 and HSD3B1, the genes involved in progesterone synthesis in placental trophoblasts . Another important signaling pathway activated upon CRH stimulation is the nitric oxide (NO)/cGMP, involved in the control of vascular tone . In human keratinocytes, upon CRH stimulation, NFKBIA degradation is diminished and the activity of NFKB is inhibited resulting in the down-regulation of NFKB-dependant genes IL2 and HSP90AA1 and inhibition of cell proliferation . The gene involved in cell survival, BCL2 is transcriptionally regulated via the PI3K/AKT .

Please access this pathway at NetSlim database.

Comments

 
NetPath - Corticotropin-releasing hormone. NetPath (http://www.netpath.org) is a collaborative project between PandeyLab at Johns Hopkins University (http://pandeylab.igm.jhmi.edu) and the Institute of Bioinformatics (http://www.ibioinformatics.org). If you use this pathway, you must cite the NetPath website until the pathway is published.
HomologyConvert 
This pathway was inferred from Homo sapiens pathway WP2355(79973) with a 96.0% conversion rate.

Quality Tags

Ontology Terms

 

Bibliography

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History

CompareRevisionActionTimeUserComment
90022view19:31, 8 October 2016AlexanderPicoModified description
89806view11:41, 6 October 2016Mkutmonfixed special characters in description
80909view15:30, 30 June 2015MkutmonNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ACACAGeneProduct
ACTH production
ADRBK2GeneProductENSBTAG00000000005 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:157
AKT1GeneProductENSBTAG00000017636 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:207
ARRB1GeneProductENSBTAG00000020485 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:408
ARRB2GeneProductENSBTAG00000035587 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:409
BCL2GeneProductENSBTAG00000019302 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:596
BIKBAGeneProductENSBTAG00000016683 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4792
BRAFGeneProductENSBTAG00000021761 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:673
CACNA1HGeneProductENSBTAG00000026461 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:8912
CAMK2AGeneProductENSBTAG00000020087 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:815
CASP12GeneProduct
CASP3GeneProductENSBTAG00000015874 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:836
CASP9GeneProductENSBTAG00000002472 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:842
CREB1GeneProductENSBTAG00000005474 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1385
CRHBPGeneProductENSBTAG00000020202 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1393
CRHGeneProductENSBTAG00000033128 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1392
CRHR1GeneProductENSBTAG00000002749 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1394
CRHR2GeneProductENSBTAG00000014381 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1395
CTNNB1GeneProductENSBTAG00000016420 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1499
CXCL8GeneProductENSBTAG00000019716 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3576
CYP11A1GeneProductENSBTAG00000006934 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1583
CYP11B1GeneProductENSBTAG00000004596 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1584
CYP17A1GeneProductENSBTAG00000004596 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1584
CYP21A2GeneProductENSBTAG00000047039 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1589
CalciumMetabolite
DAGMetabolite
ECE1GeneProductENSBTAG00000002977 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1889
ELK1GeneProductENSBTAG00000015817 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2002
ERN1GeneProductENSBTAG00000016799 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2081
FOSBGeneProductENSBTAG00000008182 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2354
FOSGeneProductENSBTAG00000004322 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2353
FOSL1GeneProductENSBTAG00000006194 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:8061
FOSL2GeneProductENSBTAG00000023929 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2355
G-gamma
GJA1GeneProductENSBTAG00000001835 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2697
GNA11GeneProductENSBTAG00000012181 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2767
GNAI1GeneProductENSBTAG00000002714 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2770
GNAI2GeneProductENSBTAG00000020645 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2771
GNAO1GeneProductENSBTAG00000003794 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2775
GNAQGeneProductENSBTAG00000009789 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2776
GNASGeneProductENSBTAG00000017475 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2778
GNAZGeneProductENSBTAG00000047664 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2781
GNB1GeneProductENSBTAG00000000215 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2782
GNB2GeneProductENSBTAG00000006495 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2783
GNB3GeneProductENSBTAG00000016043 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2784
GNB5GeneProductENSBTAG00000003762 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:10681
GRK6GeneProductENSBTAG00000043994 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2870
GSK3BGeneProductENSBTAG00000048057 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2932
HSD3BGeneProductENSBTAG00000006769 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3284
HSP90AA1GeneProductENSBTAG00000006270 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3320
IL18GeneProductENSBTAG00000000277 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3606
IL2GeneProductENSBTAG00000020883 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3558
IP3Metabolite
IVLGeneProductENSBTAG00000017827 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3713
JUNBGeneProduct
JUNBGeneProductENSBTAG00000012046 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3726
JUPGeneProductENSBTAG00000017685 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3728
KRT14GeneProductENSBTAG00000007583 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3861
KRT1GeneProductENSBTAG00000046089 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3848
MAP2K1GeneProductENSBTAG00000033983 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5604
MAP3K5GeneProductENSBTAG00000009065 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4217
MAPK14GeneProductENSBTAG00000020783 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1432
MAPK1GeneProductENSBTAG00000010312 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5594
MAPK3GeneProductENSBTAG00000016156 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5595
MAPK8GeneProductENSBTAG00000007876 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5599
MAPK9GeneProductENSBTAG00000004709 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5601
NCOA2GeneProductENSBTAG00000020312 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:10499
NFKB1GeneProductENSBTAG00000020270 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4790
NOS3GeneProductENSBTAG00000017680 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4846
NR4A1GeneProductENSBTAG00000000507 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3164
NR4A2GeneProductENSBTAG00000003650 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4929
PARP1GeneProductENSBTAG00000000837 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:142
PI3K
PIP2Metabolite
PLCG1GeneProductENSBTAG00000017584 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5335
PLCG2GeneProductENSBTAG00000002103 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5336
POMCGeneProductENSBTAG00000007897 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5443
PRKAGeneProduct
PRKAA2GeneProductENSBTAG00000018747 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5563
PRKCAGeneProductENSBTAG00000001061 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5578
PRKCBGeneProductENSBTAG00000020921 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5579
PRKCDGeneProductENSBTAG00000008719 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5580
PRKCIGeneProductENSBTAG00000001403 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5584
PRKCQGeneProductENSBTAG00000010664 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5588
PTK2GeneProductENSBTAG00000009578 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5747
RAF1ProteinENSBTAG00000045748 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5894
RAP1BGeneProductENSBTAG00000008967 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5908
RAPGEF3GeneProductENSBTAG00000006828 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:10411
RELAGeneProductENSBTAG00000013895 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5970
RHOAGeneProductENSBTAG00000004279 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:387
SP1GeneProductENSBTAG00000003021 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6667
STARGeneProductENSBTAG00000033345 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6770
SULT2A1GeneProductENSBTAG00000039971 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6822
TBX19GeneProductENSBTAG00000002952 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:9095
TCF7L2GeneProductENSBTAG00000016462 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6925
TFAP2AGeneProductENSBTAG00000001250 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:7020
TGFB1GeneProductENSBTAG00000020457 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:7040
TLR4GeneProductENSBTAG00000006240 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:7099
TRIM28GeneProductENSBTAG00000006422 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:10155
cAMPMetabolite

Annotated Interactions

No annotated interactions
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