Role and action in the pituitary corticotroph of corticotropin-releasing factor (CRF) in the hypothalamus

Corticotropin-releasing factor (CRF), produced in the hypothalamic paraventricular nucleus (PVN) in response to stress, stimulates the synthesis and secretion of adrenocorticotropin (ACTH) via CRF receptor type 1 (CRF 1 receptor) in the anterior pituitary (AP) of mammals. CRF is critical for the circadian rhythmicity of the hypothalamic–pituitary–adrenal axis and the augmented release of ACTH from the pituitary in response to the stress. A higher molecular weight form of immunoreactive β-endorphin, putative proopiomelanocortin (POMC), is increased in CRF-knockout mice (CRF KO), suggesting the important role of CRF in the processing of POMC. In fact, CRF is able to modulate the processing of POMC through changes in prohormone convertase (PC)-1 expression levels. Multiple forms of ACTH-related peptides containing unprocessed ones are present in some cases of ACTH-producing tumors, presumably without action of PC-1 under the control of CRF. Following CRF-activated stimulation of the receptor signaling, CRF 1 receptor is down-regulated and desensitized. In fact, CRF facilitates the degradation of CRF 1 receptor mRNA via the protein kinase A pathway. Prolonged agonist activation of CRF 1 receptor leads to a loss of responsiveness, or desensitization of the receptor. G protein-coupled receptor kinase 2 is involved in desensitization of CRF 1 receptor by CRF in the corticotroph.