Corticotropin Releasing Hormone Signaling

Corticotropin-Releasing Hormone (CRH) plays a major role in coordinating the behavioral, endocrine, cardiovascular, autonomic and immune mechanisms that allow mammals to adapt under both basal and stressful conditions. Their actions are mediated through activation of two types of GPCRs: CRH Receptor 1 (CRHR1) and CRHR2. CRH and its receptors are widely distributed in the central nervous system, and in a variety of peripheral tissues, including the immune, cardiovascular and reproductive systems, adrenals, lungs, liver, stomach, pancreas, small intestine, skin, and also in some types of tumors. The ubiquitous distribution of CRHRs makes it capable of activating diverse signaling mechanisms in different tissues. CRH stimulates POMC transcription and ACTH secretion. ACTH in turn controls the secretion of steroid hormones by the adrenal cortex, which affects glucose, protein, and fat metabolism. CRHR1 is implicated in mediating normal responses to stress, whereas CRHR2 is involved in fine tuning stress responses.In many tissues (e.g. brain, heart, myometrium), stimulation of either type of CRHR leads to the activation of AC and the subsequent increase in cAMP levels. However, in certain tissues (i.e. testes, placenta), CRH stimulates alternative signaling cascades, such as stimulation of phosphoinositol hydrolysis. CRHRs modulate a plethora of intracellular protein kinases, such as PKA, PKC, Akt, ERKs and p38 MAPKs, as well as other important signaling intermediates, such as Ca2+, NOS, GC, steroidogenic enzymes, prostaglandins, FasL etc. in a tissue-specific manner. These proteins in turn stimulate various transcription factors like c-Jun, c-Fos, JunD, Elk1, MEF2, and CREB which act directly on the POMC promoter and stimulate ACTH biosynthesis along with the expression of several other genes.The MAPK pathway is activated by CRH and cAMP by calcium-dependent and -independent mechanisms involving Rap1, B-Raf, MEK and ERK. PLC is also activated by CRHRs in a G-αq-dependent manner with the production of DAG and IP3, which in turn activate PKC -dependent and calcium-activated pathways respectively. The PKC pathway mediates several of the immune effects of CRH. CRH stimulates fetal adrenal steroidogenesis and prostaglandin synthesis by placenta via the PKC pathway by the activation of NOS, GC and cGMP. Production of NO by CRH brings about vasodilation. In addition, CRHR induces the transcription of the COX2 gene in fetal membranes through the involvement of the PKC pathway resulting in the release of arachidonic acid and prostaglandins.The effects of CRH on Leydig, myometrial, and hippocampal cells also involve activation of the PKC pathway by stimulating the MAPKs via Raf1 activation. The CRHR-MAPK cascade mediates the neuroprotective effects of the CRH and CRH-like peptides. The CRHR-activated PKA pathway activates BDNF expression which leads to synaptic plasticity and neurogenesis. FasL activation by CRHR-activated p38 MAPK culminates in apoptosis. In the heart and vasculature CRHRs mediate the ionotropic, vasodilatory, and anti-edema effects of CRH. In immune cells, CRH both inhibits and stimulates production of the proinflammatory cytokines (IL-1 and IL-6) by peripheral blood mononuclear cells. CRH stimulates the expression of cytokeratin1 and involucrin, leading to cell differentiation. CRH has proinflammatory effects in mast cells. It induces VEGF release in mast cells via selective activation of the cAMP-PKA-p38 MAPK signaling pathway. ACTH secretion by CRHR pathway is augmented by its crosstalk with the Shh pathway. At high levels CRH causes anxiety, sleep disruption and adverse changes in cardiovascular, metabolic and immune functions.