Corticotropin-releasing factor (CRF), a peptide first isolated from mammalian brain, is critical in the regulation of the pituitary-adrenal axis, and in complementary stress-related endocrine, autonomic and behavioural responses. Fish urotensin I and amphibian sauvagine were considered to be homologues of CRF until peptides even more closely related to CRF were identified in these same vertebrate classes. We have characterized another mammalian member of the CRF family and have localized its urotensin-like immunoreactivity to, and cloned related complementary DNAs from, a discrete rat midbrain region. The deduced protein encodes a peptide that we name urocortin, which is related to urotensin (63% sequence identity) and CRF (45% sequence identity). Synthetic urocortin evokes secretion of adrenocorticotropic hormone (ACTH) both in vitro and in vivo and binds and activates transfected type-1 CRF receptors, the subtype expressed by pituitary corticotropes. The coincidence of urotensin-like immunoreactivity with type-2 CRF receptors in brain, and our observation that urocortin is more potent than CRF at binding and activating type-2 CRF receptors, as well as at inducing c-Fos (an index of cellular activation) in regions enriched in type-2 CRF receptors, indicate that this new peptide could be an endogenous ligand for type-2 CRF receptors.

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In the nematode Caenorhabditis elegans, dauer formation, stress resistance, and longevity are determined in part by DAF-2 (insulin receptor-like protein), AGE-1 (phosphatidylinositol-3-OH kinase catalytic subunit), and DAF-16 (forkhead transcription factor). Mutations in daf-2 and age-1 result in increased resistance to heat, oxidants, and UV. We have discovered that daf-2 and age-1 mutations result in increased Cd and Cu ion resistance in a 24 h toxicity assay. Lethal concentration (LC50) values for Cd and Cu ions in daf-2 and age-1 mutants were significantly (P<0.001) higher than in wild-type nematodes. However, LC50 values in daf-16;age-1 mutants were not significantly different, implying that metal resistance is influenced by a DAF-16-related function. As metallothionein (MT) proteins play a major role in metal detoxification, we examined the expression of MT genes both under noninducing conditions and after exposure to sublethal and acute heavy metal stress. MT1 mRNA levels were significantly (P<0.05) higher in daf-2 mutants compared to age-1 mutants and wild-type C. elegans under basal conditions. After 10 mM Cd treatment, induction of MT1 and MT2 mRNA was three- and twofold higher, respectively, in daf-2 mutant worms than in wild-type. However, a sublethal concentration of Cd (0.1 mM) resulted in even higher (three- to sevenfold) levels of both MT mRNAs in all strains. Cu did not induce MT1 or MT2 mRNAs. These results are consistent with a model in which the insulin-signaling pathway determines life span through regulation of stress protein genes

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Most vertebrate species have more than one form of gonadotropin-releasing hormone (GnRH) in their brains, but it is not clear whether each form has a distinct function. We report that sea bream (Sparus awrta) brains have three forms of GnRH, one of which is described herein and is called sea bream GnRH (sbGnRH). The primary structures of two forms were determined by Edman degradation and mass spectral analysis. The amino acid sequence of sbGnRH is pGlu-His-Trp-Ser-Tyr-Gly-Leu-Ser-Pro-Gly-NH2. The second peptide is identical to a form originally isolated from chicken brains (cGnRH-II): pGlu-His-Trp-Ser-His-Gly-Trp-Tyr-ProGly-NH2. cGnRH-H is the most ancient form of GnRH identified to date in jawed fish and the most prevalent form throughout the vertebrates. The third form of GnRH has previously been identified as salmon GnRH by cDNA studies and is confirmed here by chromatographic and immunological studies. Phylogenetic distribution of GnRH peptides suggests sbGnRH arose in the perch-like fish as a gene duplication of the existing cGnRH-ll or salmon GnRH genes. All three identified GnRH peptides were synthesized and shown to release gonadotropin in vivo in the sea bream. The dominant form of GnRH stored in the pituitary was sbGnRH. Not only was the content ofsbGnRH 500-fold greater than that ofsalmon GnRH but also cGRH-II was not deeced in the pituitary. The latter evidence suggests that sbGnRH is the endogenous releaser of gonadotropin II.Gonadotropin-releasing hormone (GnRH) is both a releaser of gonadotropins and a neuromodulator (1, 2)