Physiology, pharmacology, and therapeutic relevance of urocortins in mammals: Ancient CRF paralogs

Abstract

Urocortins, three paralogs of the stress-related peptide corticotropin-releasing factor (CRF) found in bony fish, amphibians, birds and mammals, have unique phylogenies, pharmacologies, and tissue distributions. As a result and despite a structural family resemblance, the natural functions of urocortins and CRF in mammalian homeostatic responses differ substantially. Endogenous urocortins are neither simply counterpoints nor mimics of endogenous CRF action. In their own right, urocortins may be clinically relevant molecules in the pathogenesis or management of many conditions, including congestive heart failure, hypertension, gastrointestinal and inflammatory disorders (irritable bowel syndrome, active gastritis, gastroparesis, rheumatoid arthritis), atopic/ allergic disorders (dermatitis, urticaria, asthma), pregnancy and parturition (preeclampsia, spontaneous abortion, onset and maintenance of effective labor), major depression and obesity. Safety trials for intravenous urocortin treatment have already begun for the treatment of congestive heart failure. Further understanding the unique functions of urocortin 1, urocortin 2 and urocortin 3 action may uncover other therapeutic opportunities. KeywordsUrocortin 1 or urocortin 2 or urocortin 3 or stresscopin or stresscopin-related peptide; corticotropinreleasing factor or CRF or corticotropin-releasing hormone or CRH or corticoliberin; stress response; peptide; anxiety or depression; pregnancy; labor or parturitition; food intake or energy balance or obesity; inflammation or immune system; salt or fluid balance; cardiovascular or hypertension or heart failure; gastrointestinal motility or irritable bowel syndrome

Regulation of corticotropin-releasing factor and urocortin 2/3 mRNA by leptin in hypothalamic N39 cells

“…Ucn2 and Ucn3 prohormones were identified in the human genome database and in mouse genomic DNA, respectively [27,35,50], which led to predictions regarding the existence and identity of endogenous peptides [20]. Ucn2 and Ucn3 are more similar to each other than they are to CRF, and both have very high affinity for the CRF type 2 receptor (CRF 2 receptor) but little to none for the CRF 1 receptor [33,38,48,57].…”

Urocortin2 inhibits tumor growth via effects on vascularization and cell proliferation

“…anti-angiogenic ͉ cancer ͉ CRF ͉ peptide ͉ CRFR2 T he corticotropin-releasing factor (CRF) pathway, initially defined as a hypothalamic neuroendocrine pathway controlling the release of ACTH from the pituitary, is now known to involve at least two distinct G protein-linked receptors, several receptor splice variants, and an assortment of unique peptide ligands and to be present in multiple peripheral organs and tissues (1)(2)(3)(4)(5)(6). The peripheral roles of this pathway and its various components are only recently becoming recognized, and much is not known or understood.…”

“…The peripheral roles of this pathway and its various components are only recently becoming recognized, and much is not known or understood. It has become apparent, however, that this pathway and its components are involved in a wide array of physiological and potentially pathophysiological processes, and the CRF pathway presents, therefore, a very promising clinical therapeutic target (4). Global deletion of the CRFR2 receptor causes a heightened stress response in mice, a finding attributed to CNS activities of this pathway (5,7).…”

Urocortin 2 treatment is protective in excitotoxic retinal degeneration

“…Urocortins are the ancient paralogs of CRF-Rs (14). In the retina, CRF-like immunoreactivity has been described in horizontal, amacrine and ganglion cells and their processes (35)(36)(37)(38)(39).…”

“…Ucn 2 and Ucn 3 have similar structures and both peptides act as a preferential or selective CRF2-R agonists, leading to their designation as the selective CRF2-R agonists. High levels of Ucn 2 and its receptor have been observed in the heart, lung, muscle, stomach, blood cells, skin, placenta and hypothalamus, pituitary and adrenal medulla (14). Not surprisingly, urocortins have been proposed to participate in many physiological functions, including effects in the nervous system.…”