New insights into urotensin endocrinology: From fish to man

Abstract

Theurotensins(UIandUII)werefirstidentifiedinthecau-dal neurosecretory system (CNSS) of fish, a unique neuroen-docrine structure located in the terminal segments of thespinalcord.Morerecently,homologuestobothpeptideshavebeenidentifiedinmammalsand,whileresearchcontinuesintotheroleoftheCNSSinfish,interestintheactionsoftheuro-tensins in other vertebrates, including man, has grown.Steve Douglas reviewed the history of UII research inmammals, following the identification of its ‘‘orphan’’ G-protein coupled UT receptor, GPR14. Both UII and UTreceptor are localised in regions of the mammalian brain,as well as in non-neural tissues such as cardiovascular andrenal tissues. The potent vasoconstrictor actions of UII ledto the search for antagonists that might be effective in dis-ease states such as hypertension, congestive heart failureand diabetes mellitus. Current animal studies give causefor optimism that this ‘‘from gills to pills’’ approach willlead to novel and improved clinical tools, such as in patientswhose hypertension cannot currently be controlled. Forexample, UT receptor antagonists have been shown to behighly protective against heart failure in animal models.Continuing on this theme, Nick Ashton and Alaa Abdel-Razikreported renal effects of UII in the rat. UT receptors arepresent in renal medulla and UII appears in relatively highconcentrations in urine, suggesting that it is activelysecreted. Both haemodynamic and tubular actions of UIIare indicated, leading to reduced urinary output, and theconverse effects were seen with a UT receptor antagonist,urantide.Isabelle Lihrmann gave a comparative overview of UII,UII-related peptide (URP) and UT receptor distributionthroughout the vertebrates. mRNA expression profilesfor UII appear to be well conserved throughout the verte-brate series from dipneusts to mammals, with the highestlevel of expression in spinal cord, localised to motoneuronsin the ventral horn. A similar distribution is seen for URPexpression, apart from some differential expression in cra-nial nuclei. The UT receptor is widely expressed in theCNS and peripheral tissues, including skeletal muscle. Inaddition to central actions of the peptides with respect tocardiovascular control, these findings perhaps support alocomotory role for UII. In addition a role for URP inarousal, via the reticular activating system, was proposed.Jean-Claude Le Mevel reported investigations into thecentral actions of UI and UII. The two peptides had differ-ential effects when injected intracerebroventricularly introut. UI, but not UII, caused increases in blood pressureand ventilatory output. Both peptides enhanced locomotoractivity (swimming), though effects of UII were more longlasting. These findings suggest that the urotensins haveimportant regulatory functions within the brain, whichmay also be of relevance to mammalian studies.A comparative genomics study by Herve Tostivint,examined the relationship between UII/URP and somato-statin (SS)-related peptides, previously considered to beunrelated gene products. These peptides display a similarcyclic structure and precursor organisation throughoutthe vertebrates. Analysis of predicted gene duplicationsand chromosomal locations has led to an evolutionarymodel supporting a single ancestral gene superfamily forUII- and SS-related genes, raising questions regarding theevolution of UII and its function in lower vertebrates.TheCNSSofteleost fish waspresented asa model systeminwhichtoexamineneurosecretorymechanismsand uroten-sin physiology. In zebrafish (Caroline Parmentier), neurose-cretory Dahlgren cells display immunoreactivity for both UIand UII. Most cells do not colocalise the two peptides.However, in some, UI and UII are colocalised even at thelevel of secretory terminals and vesicles. Detailed morpho-logical observations indicate further secretory roles for theCNSS that have yet to be defined. With its characterisedgenome, the zebrafish provides the genetic tools with whichto dissect CNSS function and other functional aspects ofurotensin-related physiology. Sarah Alderman described atissue mapping study of the expression patterns of UI, cor-ticotropin-releasing factor (CRF), and CRF-binding proteininadultanddevelopingzebrafish. All threeshowwidespreadbut highly localised distribution within the CNS, including