Urotensin related peptides、尿緊張素相關(guān)肽

Definition

Urotensin II (UII) is a piscine neuropeptide. Urotensin-related peptide (URP) is a paralog of UII in that it contains the six amino acid ring structures found in UII.

Discovery

In 2004, Mori and Fujino discovered Urotensin II-related peptide, the endogenous ligand for the urotensin II receptor, by monitoring UII-immunoreactivity in the rat brain1.

Structural Characteristics

UII is the most potent vasoconstrictor peptide and recognized as the endogenous ligand of the orphan G protein-coupled receptor GPR14. UII-related peptide (URP) isolated from the rat brain has been shown to have amino acid sequence as H-Ala-Cys-Phe-Trp-Lys-Tyr-Cys-Val-OH. In order to study the structure–function relationships of URP, a series of URP analogs were synthesized and measured their binding affinity on hGPR14-transfected cells and their contractile activity in a rat aortic ring bioassay2. It was found that alanine substitution of each residue of URP significantly reduced the binding affinity and the contractile activity of the peptides, except for the Ala8-substituted analog that retained biological activity. Most importantly, D-scan of URP revealed that [D-Trp4]URP abrogated and [D-Tyr6]URP partially suppressed the UII-evoked contractile response. [Orn5]URP, which had very low agonistic efficacy, was the most potent antagonist in this series. The solution structure of URP has been determined by 1H NMR spectroscopy and molecular dynamics. URP exhibited a single conformation characterized by an inverse ?-turn comprising residues Trp-Lys-Tyr which plays a crucial role in the biological activity of URP2.

Mode of Action

Earlier repots show that UII and URP genes belong to the same superfamily as the somatostatin gene. It has been previously shown that somatostatin activates the UTR. In contrast, the possible interaction between UII and URP and somatostatin receptors has remained to be analyzed. A study investigated the effects of UII and URP on cell proliferation and free cytosolic Ca2+ concentration ([Ca2+]i) in CHO-K1 cells stably expressing the porcine somatostatin receptor subtypes sst2 and sst5. Results show that both UII and URP induce stimulation of cell proliferation mediated by sst2 receptors and UII provokes inhibition of cell proliferation mediated by sst5 receptors. UII and URP also provoked an increase of [Ca2+]i in both sst2- and sst5-transfected cells. Together, this data demonstrate that UII and URP directly activate sst2 and sst5 and thus mimic the effect of somatostatin on its cognate receptors3.

Functions

Urotensin II and urotensin II-related peptide (URP) in cardiac ischemia-reperfusion injury: A report describes the direct cardiac effects of UII and URP in ischemia-reperfusion injury. Isolated perfused rat hearts were subjected to no-flow global ischemia for 45 min after 30 min preconditioning with either 1 nM rUII or 10 nM URP. Both UII- and URP-induced significant vasodilation of coronary arteries before and after ischemia. Rat UII alone lowered contractility prior to ischemia. Specific assay of perfusate revealed rUII and URP both significantly inhibited reperfusion myocardial creatine kinase (CK) release and atrial natriuretic peptide (ANP) secretion. Antagonism of the UT receptor with 1 µM palosuran caused a significant increase in perfusion pressure (PP) prior to and post-ischemia. Furthermore, palosuran significantly inhibited reductions in both PP and myocardial damage marker release induced by both rUII and URP. In conclusion, this study suggests that rUII and URP reduce cardiac ischemia-reperfusion injury by increasing flow through the coronary circulation, reducing contractility and therefore myocardial energy demand, and inhibiting reperfusion myocardial damage. Thus, UII and URP present as novel peptides with potential cardioprotective actions4.

Cardiovascular effects of native and non-native urotensin II and urotensin II-related peptide on rat and salmon hearts: In an experiment the effects of native and non-native urotensin II and urotensin II-related peptide on isolated heart preparations of Chinook salmon and Sprague–Dawley rats were studied. Native rat UII caused potent and sustained, dose-dependent dilation of the coronary arteries in the rat, whereas non-native UII (human and trout UII) showed attenuated vasodilation. Rat URP dilated rat coronary arteries, with 10-fold less potency compared with rUII. In salmon, native trout UII caused sustained dilation of the coronary arteries, while rat UII and URP caused significant constriction. N?-nitro-l-arginine methyl (l-NAME) and indomethacin significantly attenuated the URP and rat UII-induced vasodilation in the rat heart. This shows that UII is a coronary vasodilator5, an action that is species form specific. Also, this study provides the evidence for cardiac actions of URP, possibly via mechanisms common with UII 5.

References

1.Mori M, Fujino M (2004). Urotensin II-related peptide, the endogenous ligand for the urotensin II receptor in the rat brain. Peptides, 25(10):1815-1818.

2.Chatenet D, Dubessy C, Leprince J, Boularan C, Carlier L, Ségalas-Milazzo I, Guilhaudis L, Oulyadi H, Davoust D, Scalbert E, Pfeiffer B, Renard P, Tonon MC, Lihrmann I, Pacaud P, Vaudry H (2004). Structure–activity relationships and structural conformation of a novel urotensin II-related peptide. Peptides, 25(10):1819-1830.

3.Malagon MM, Molina M, Gahete MD, Duran-Prado M, Martinez-Fuentes AJ, Alcain FJ, Tonon MC, Leprince J, Vaudry H, Castaño JP, Vazquez-Martinez R (2008). Urotensin II and urotensin II-related peptide activate somatostatin receptor subtypes 2 and 5. Peptides, 29(5):711-720.

4.Prosser HC, Forster ME, Richards AM, Pemberton CJ (2008). Urotensin II and urotensin II-related peptide (URP) in cardiac ischemia-reperfusion injury. Peptides, 29 (5):770-777.

5.Prosser HC, Leprince J, Vaudry H, Richards AM, Forster ME, Pemberton CJ (2006). Cardiovascular effects of native and non-native urotensin II and urotensin II-related peptide on rat and salmon hearts. Peptides, 27(12):3261-3268.