Corticotropin-releasing hormone signaling pathway (WP2355)

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-dependent 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 [http://www.netpath.org/netslim/CRH_pathway.html NetSlim] database. Proteins on this pathway have targeted assays available via the [https://assays.cancer.gov/available_assays?wp_id=WP2355 CPTAC Assay Portal]
last edited

Authors

NetPath, Khanspers, MaintBot, Ddigles, Zari, MirellaKalafati, Mkutmon, AlexanderPico, AMTan, Fehrhart, L Dupuis, and Eweitz

Cited In

Organism

Homo sapiens

Communities

Annotations

Disease Ontology: major depressive disorder Alzheimer's disease Parkinson's disease anorexia nervosa

Pathway Ontology: corticotropin-releasing hormone signaling pathway

Participants

Label Type Compact Identifier
PRKCQ GeneProduct ncbigene:5588
JUN GeneProduct ncbigene:3726
JUNB GeneProduct ncbigene:3727
PRKAA2 GeneProduct ncbigene:5563
FOSL1 GeneProduct ncbigene:8061
TLR4 GeneProduct ncbigene:7099
SP1 GeneProduct ncbigene:6667
NCOA2 GeneProduct ncbigene:10499
CRHBP GeneProduct ncbigene:1393
NR4A1 GeneProduct ncbigene:3164
JUND GeneProduct ncbigene:3728
CRH GeneProduct ncbigene:1392
IL18 GeneProduct ncbigene:3606
ACACA GeneProduct ncbigene:31
FOSL2 GeneProduct ncbigene:2355
RHOA GeneProduct ncbigene:387
CACNA1H GeneProduct ncbigene:8912
PTK2 GeneProduct ncbigene:5747
FOS GeneProduct ncbigene:2353
IL8 GeneProduct ncbigene:3576
FOSB GeneProduct ncbigene:2354
NOS3 GeneProduct ncbigene:4846
TRIM28 GeneProduct ncbigene:10155
PRKA GeneProduct None
NR4A1 GeneProduct ncbigene:3164
PRKCI GeneProduct ncbigene:5584
PRKCD GeneProduct ncbigene:5580
HSD3B1 GeneProduct ncbigene:3283
TCF4 GeneProduct ncbigene:6925
TFAP2A GeneProduct ncbigene:7020
CTNNB1 GeneProduct ncbigene:1499
ACTH production Unknown None
MAPK3 GeneProduct ncbigene:5595
IL2 GeneProduct ncbigene:3558
KRT1 GeneProduct ncbigene:3848
MAPK9 GeneProduct ncbigene:5601
NR4A2 GeneProduct ncbigene:4929
CRHR2 GeneProduct ncbigene:1395
MAPK1 GeneProduct ncbigene:5594
CRH GeneProduct ncbigene:1392
SP1 GeneProduct ncbigene:6667
CYP11A1 GeneProduct ncbigene:1583
HSP90AA1 GeneProduct ncbigene:3320
IVL GeneProduct ncbigene:3713
CRHR1 GeneProduct ncbigene:1394
NR4A1 GeneProduct ncbigene:3164
TFAP2A GeneProduct ncbigene:7020
CRH GeneProduct ncbigene:1392
CRHR1 GeneProduct ncbigene:1394
EPAC GeneProduct ncbigene:10411
CTNNB1 GeneProduct ncbigene:1499
KRT14 GeneProduct ncbigene:3861
Receptor GeneProduct ncbigene:7040
Ligand GeneProduct ncbigene:7040
Protein Protein ncbigene:5894
RELA GeneProduct ncbigene:5970
PRKCB GeneProduct ncbigene:5579
PRKCA GeneProduct ncbigene:5578
GNAQ GeneProduct ncbigene:2776
CREB1 GeneProduct ncbigene:1385
PRKA GeneProduct None
cAMP Metabolite wikidata:Q210041
GNB5 GeneProduct ncbigene:10681
GNB3 GeneProduct ncbigene:2784
GNB2 GeneProduct ncbigene:2783
GNB1 GeneProduct ncbigene:2782
ADRBK2 GeneProduct ncbigene:157
GNA11 GeneProduct ncbigene:2767
GNAO1 GeneProduct ncbigene:2775
GNAS GeneProduct ncbigene:2778
GNAI2 GeneProduct ncbigene:2771
GNAI1 GeneProduct ncbigene:2770
DAG Metabolite wikidata:Q161466
IP3 Metabolite wikidata:Q26998374
PIP2 Metabolite wikidata:Q3083814
MAP2K1 GeneProduct ncbigene:5604
BRAF GeneProduct ncbigene:673
RAP1B GeneProduct ncbigene:5908
PLCB3 GeneProduct ncbigene:1394
PLCG2 GeneProduct ncbigene:5336
PLCG1 GeneProduct ncbigene:5335
GSK3B GeneProduct ncbigene:2932
PARP1 GeneProduct ncbigene:142
CASP9 GeneProduct ncbigene:842
CASP3 GeneProduct ncbigene:836
CASP12 GeneProduct ncbigene:100506742
MAPK8 GeneProduct ncbigene:5599
MAP3K5 GeneProduct ncbigene:4217
ERN GeneProduct ncbigene:2081
CYP21A2 GeneProduct ncbigene:1589
CYP17A1 GeneProduct ncbigene:1584
STAR GeneProduct ncbigene:6770
CYP11B1 GeneProduct ncbigene:1584
CYP11A1 GeneProduct ncbigene:1583
CAMK2A GeneProduct ncbigene:815
HSD3B2 GeneProduct ncbigene:3284
GRK6 GeneProduct ncbigene:2870
ADRBK2 GeneProduct ncbigene:157
ECE1 GeneProduct ncbigene:1889
NFKBIA GeneProduct ncbigene:4792
GJA1 GeneProduct ncbigene:2697
CRHR2 GeneProduct ncbigene:1395
ARRB1 GeneProduct ncbigene:408
SULT2A1 GeneProduct ncbigene:6822
ADRBK2 GeneProduct ncbigene:157
CRH GeneProduct ncbigene:1392
ARRB2 GeneProduct ncbigene:409
RELA GeneProduct ncbigene:5970
BCL2 GeneProduct ncbigene:596
PI3K Unknown None
AKT1 GeneProduct ncbigene:207
POMC GeneProduct ncbigene:5443
NR4A2 GeneProduct ncbigene:4929
FOS GeneProduct ncbigene:2353
Calcium Metabolite wikidata:Q23905776
ARRB1 GeneProduct ncbigene:408
ARRB2 GeneProduct ncbigene:409
ECE1 GeneProduct ncbigene:1889
CRH GeneProduct ncbigene:1392
CRHR1 GeneProduct ncbigene:1394
CRHR2 GeneProduct ncbigene:1395
CRH GeneProduct ncbigene:1392
CRHR1 GeneProduct ncbigene:1394
CRH GeneProduct ncbigene:1392
GNAZ GeneProduct ncbigene:2781
ELK1 GeneProduct ncbigene:2002
TBX19 GeneProduct ncbigene:9095
FOS GeneProduct ncbigene:2353
G-gamma Unknown None
NFKB1 GeneProduct ncbigene:4790
NFKB1 GeneProduct ncbigene:4790
NFKB1 GeneProduct ncbigene:4790
MAPK14 GeneProduct ncbigene:1432
NR4A1 GeneProduct ncbigene:3164
CRH GeneProduct ncbigene:1392
CRHBP GeneProduct ncbigene:1393

References