Urocortins

Urocortins
Definition
Urocortin (UCN) is a 40 amino acid peptide, member of the corticotropin-releasing hormone (CRH)-related peptides that has been reported to have cardiac inotropic and hypertrophic effects.

Discovery
In 1995, Vaughan and colleagues described the discovery of a CRF-related peptide expressed in rat brain known as UCN, named after its peptide homology to both the teleost hormone urotensin and to mammalian CRF and because it possesses biological activity exhibited by both of these peptides1.

Structural Characteristics
The sequence of UCN has been determined in both rats and humans. In rat, UCN was identified using a library derived from rat midbrain and a carp urotensin cDNA probe. A full-length cDNA was described1 and encoded a putative 40-amino acid peptide that was related to CRF. The human form was subsequently identified using a cDNA probe encoding the peptide region of rat urocortin and screening a human genomic library 2. The resulting putative peptide demonstrated 88% identity to rat at the nucleotide level and 95% identity at the amino acid level. In both species, urocortin is a 40-amino acid residue single-chain polypeptide; the two forms differ by only two amino acids2 at positions 2 (Asn to Asp) and 4 (Ser to Pro). In addition to the homology between the species, the deduced amino acid sequence of rat and human UCN exhibits sequence identity with urotensin I (63%) and human CRF (45%). Consistent with the other CRF-related peptides, UCN is also amidated at its carboxy terminal, again suggesting the importance of amidation to this family of peptides.

Mode of Action
UCN binds with high affinity to all the known effectors of CRF function, including CRF 1, CRF2a, CRF2ß receptors, and CRF-binding protein. UCN binds to cells stably transfected with the CRF1, CRF2a, or CRF2ß receptors with affinities in the 100 to 500 pM range and has 100 pM affinity1 for the CRF-BP. In vitro studies, urocortin stimulates cAMP accumulation in cells transfected with either CRF receptor subtype, and is extremely potent in stimulating ACTH release from cultured anterior pituitary cells1. The effects on the CRF1 receptor subtype are comparable to the effects of CRF itself; however, the activities observed at both CRF2 receptor isoforms are approximately tenfold more potent than CRF itself1, 2. Furthermore, the presence of CRF- Binding Protein can decrease the ability of urocortin to stimulate ACTH release in vitro2.

Functions
Central administration of urocortin inhibits vasopressin release in conscious rats: UCN is a new mammalian member of the CRF family and supposed to be an endogenous ligand for type 2 CRF receptors. In a study, the effect of centrally-administered UCN on arginine vasopressin (AVP) release in conscious rats was examined. It was found that intracerebroventricular (i.c.v.) injection of UCN (5.0 µg/rat) significantly attenuated AVP release induced by hyperosmolality at 30 min after the injection. In contrast, CRF (5.0 µg/rat) injected i.c.v. had no significant effect on AVP release. These results suggest that central UCN play an inhibitory role in osmoregulation of AVP release3.

UCN expression in human pituitary gland and pituitary adenoma (as an autocrine or a paracrine regulator): In a study, urocortin expression in human anterior pituitary gland and pituitary adenomas was examined by RIA, high performance liquid chromatography, immunohistochemistry, messenger ribonucleic acid (mRNA) in situ hybridization, and reverse transcriptase-PCR. Furthermore, UCN was immunostained in 52 cases of human anterior pituitary adenomas, including GH-producing adenomas (n = 14), ACTH-producing adenomas (n = 13), PRL-producing adenomas (n = 11), and nonfunctioning hormonally inactive adenomas (n = 14). No urocortin immunoreactivity was detected in these adenoma cells, except for one case of GH-producing adenoma and one case of nonfunctioning adenoma. We also performed mRNA in situ hybridization in 27 adenomas. The results indicate that urocortin is synthesized in human anterior pituitary cells and may play an important role in biological features of normal pituitary gland, possibly as an autocrine or a paracrine regulator4.

References
1. Vaughan J, Donaldson C, Bittencourt J, Perrin M H, Lewis K, Sutton S, Chan R, Turnbull AV, Lovejoy D, Rivier C (1995). Urocortin, a mammalian neuropeptide related to fish urotensin I and to corticotropin-releasing factor. Nature, 378(6554):287-292.
2. Donaldson CJ, Sutton SW, Perrin MH (1996). Cloning and characterization of human urocortin. Endocrinology, 137:2167-2170.
3. Kakiya S, Yokoi H, Arima H, Iwasaki Y, Oki Y, Oiso Y (1998). Central administration of urocortin inhibits vasopressin release in conscious rats. Neuroscience Letters., 248 (2): 144-146.
4. Lino K, Sasano H, Oki Y, Andoh N, Shin RW, Kitamoto T, Totsune K, Takahashi K, Suzuki H, Nagura H, Yoshimi T (1997). Urocortin expression in human pituitary gland and pituitary adenoma. J. Clin. Endocrinol. Metab., 82(11):3842-3850.

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