Corticotropin-releasing factor (CRF), also known as corti-cotropin-releasing hormone (CRH), orchestrates the stress response in the endocrine, autonomic, immune, and behavioral systems through the activation of the hypothalamic-pituitary-adrenal (HPA) axis and extrahypothalamic pathways. The peptide itself is highly conserved between species, and its evolutionary role is to mobilize energy stores and appropriate behavior(s) in response to a stressor. It has since evolved to regulate a variety of responses to stress. CRF was first isolated and characterized by Vale and colleagues in 1981. Due to the similarity in sizes of ACTH and CRF and limits on detection techniques, purification was performed on approximately 490,000 sheep (ovine) hypothalami in order to generate enough samples for isolation. This was part of an ongoing study elucidating a variety of hypotha-lamic peptides. In the majority of studies, the CRF system has consistently been shown to be dysregulated in many patients suffering from a variety of psychiatric illness including post-traumatic stress disorder (PTSD), early life trauma, and major depressive disorder (MDD) (Nemeroff et al. 1984). In a few studies, the dysregulation of CRF activity has also been implicated in anorexia nervosa and Alzheimer's disease. During pregnancy, CRF plasma levels spike during the third trimester and have been implicated in parturition. The variety of molecular and behavioral responses orchestrated by this single peptide defines it as the central focus of stress research today.
CRF belongs to a family of ► neuropeptides including sauvagine (a peptide secreted from the skin of a South American frog Pyllomedusa sauvagei), the urocortins (endogenous neuropeptides with effects similar to those of CRF), and urotensin (a peptide secreted by the Goby fish). The CRF gene was cloned by Furutani and colleagues 2 years after the isolation and characterization of CRF itself and is expressed in diverse animal species, from zebrafish to all higher mammals. Human CRF is localized to the long arm of chromosome 8 at position q13.
The CRF gene is first activated by transcription factors to produce a 196 amino acid polypeptide. The polypep-tide is posttranslationally cleaved at the N-terminus at position 147. The C-terminus is cleaved at amino acids 195-196 and undergoes posttranslational ► amidation. The importance of amidation is not clearly understood; however, sauvagine and urocortin, which also bind and activate CRF receptors, are amidated (Petrusz and Merchenthaler 1992). In vitro receptor binding experiments studying CRF receptors have shown that deami-dated CRF has reduced binding affinity for the CRF receptor, clearly demonstrating an important albeit elusive role for amidation. The mature product is a 41 amino acid neuropeptide with a molecular weight of 4,758.4 Da
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