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 (1). CRH is the principal mediator of endocrine stress response (2). CRH also plays a significant role in inflammatory responses (3, 4), hemodynamic actions (5), stromal cell decidualization during estrus cycle (6), implantation of blastocyst (7), maintenance of pregnancy, onset of labor (8) and neuroprotection (9). Excess secretion of CRH during severe depression and its association with increased levels of cortisol have been observed (10). CRH has also been reported to be involved in anxiety disorders (11), anorexia nervosa (12). Decrease in cortical CRH content has been observed in Alzheimer’s disease (13) and Parkinson’s disease (14).

The actions of CRH are mediated through class II/secretin-like family type of G-protein coupled receptor (GPCR) called the CRH receptors (CRHR) (15). CRH is a high affinity ligand of CRHR1 and also binds to CRHR2 but with lower affinity (16, 17). CRH receptors do not have any intrinsic kinase activity and transduce the signal via the heterotrimeric G- proteins (18). The CRH receptors are rapidly desensitized by G-protein-coupled receptor kinase (GRK) and ß-arrestin mechanisms in the presence of high concentrations of CRH (19). Binding of CRH to CRH receptor induces a conformational change in the receptor by activating it. This further activates Ga-subunit and its subsequent dissociation from the Gß? dimer. CRH receptors on interaction with Ga-subunit of different G-proteins such as Gas, Gai/o, Gaq/11 activate numerous downstream signaling cascades and result in the induction of various cellular responses (20). 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 ß-endorphin. ACTH, in turn, stimulates the secretion of glucocorticoids from adrenal glands and thereby mediates changes associated with stress response (2, 21). CREB also regulates genes containing the Ca 2+/cAMP response element such as FOS (9). 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 (20). Activation of cAMP/PKA can also induce the expression of enzymes involved in dehydroepiandrosterone sulfate and cortisol production (22, 23). 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 (24). MAPK14 is involved in CRH-induced inhibition of IL-18 expression in human keratinocytes (25). The CRHR1/PKA/ ERK signaling activate the transcription factors - ELK1 (26), SP1 and TFAP2A (27). SP1 and TFAP2A up-regulates the expression of ADRBK2, which causes the desensitization of CRHR1 receptors (28).

The PLC/PKC pathway is activated by coupling of the CRH receptors to the Gaq/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 (29). This cascade also inhibits the expression of CYP11A1 and HSD3B1, the genes involved in progesterone synthesis in placental trophoblasts (30).

Another important signaling pathway activated upon CRH stimulation is the nitric oxide (NO)/cGMP, involved in the control of vascular tone (31). 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 (32). The gene involved in cell survival, BCL2 is transcriptionally regulated via the PI3K/AKT (33).

References

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