s, 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. To see the ontology report for annotations, GViewer and downloads, click here...(less)