UROTENSIN-II

Human prepro-UII consists of 124 amino acid residues with bioactive mature UII at the C-terminus.5 Human UII consists of 11 amino acid residues with a cyclic structure of fully conserved six amino acid residues (CYWKYC) flanked by two cysteine residues, which are responsible for the majority of its biological activities; the N-terminal portion shows low sequence identity between species. URP is a cyclic octapeptide whose sequence differs by only one amino acid residue from that of the C-terminal region of human UII. Human UII: Mr 1388.6; pI 4.37. Human URP: Mr 1017.2; pI 8.09. Freely soluble in water, ethanol, and 20% acetonitrile/water.

The human UII gene is located on chromosome1 (1q36) and contains five exons. Human UII mRNA has 551bp of nucleotides. The human URP gene is found at 3q28 and contains five exons. The human URP mRNA has 439 bp. The UII and URP genes originate from the same ancestral gene, as do the somatostatin and cortistatin genes.

UII mRNA is detected most abundantly in the brain and spinal cord of fish, frogs, and mammals. In the frog brain, the transcripts are found in the trochlear nucleus, facial motor nucleus, abducens nucleus, glossopharyngeal nucleus, and hypoglossal nucleus. In human peripheral tissues, UII mRNA has been detected in the kidney, spleen, pancreas, small intestine, thymus, prostate, pituitary gland, and adrenal gland. In teleosts, UII and URP mRNAs are abundantly expressed in the caudal neurosecretory system (CNSS) and medulla oblongata.

UII is released depending on intracellular Ca2+ from the motoneuron terminal. Plasma UII concentrations rise in some diseases such as heart failure, essential hypertension, renal disease, diabetes, and liver cirrhosis. In the flounder, plasma UII levels are higher in seawater (SW)-acclimated fish than in freshwater (FW) ones, and decrease after the transfer of SW-acclimated fish to FW.

UII binds the orphan receptor GPR14 with high affinity, and the receptor was renamed a UII receptor (UTR). The UTR belongs to the class A, rhodopsin-like GPCR family, and shares high sequence identity with somatostatin receptors. Structural characteristics of the receptor include two potential N-glycosylation sites in the N-terminal domain and two cysteine residues in the first and second extracellular loops. Human UTR has 389 amino acid residues with Mr of 42,130. UII and URP both activate UTR with similar potency. UTR is expressed in various human tissues, notably in the cardiovascular system, including the left atrium, ventricle, coronary artery, and aorta, and in the spleen, kidney, urinary bladder, and skeletal muscle. Recent studies revealed that UTR is expressed in the hyaline chondrocytes and leukocytes in mammals and amphibians.

The UTR is coupled to the Gαq/11 signal transduction pathway, the activation of which leads to an increase in inositol triphosphate and the mobilization of intracellular Ca2+. Vasoconstriction and smooth muscle contraction by UII involve small GTPase RhoA and its downstream effector Rho-kinase, phospholipase C, protein kinase C, tyrosine kinase, and PKC-independent phosphorylation of the myosin light chain (MLC-2) as well as the Ca2+-calmodulin/MLC kinase system, extracellular signal-regulated kinase (ERK), and p38 mitogen-activated protein kinase. The UII-induced mitogenic/hypertrophic response is mediated via the ERK activation pathway and the RhoA/Rho kinase pathway.

UII induces the vasoconstriction, migration, and proliferation of vascular smooth muscle cells and leukocytes. UII also induces NO synthesis in the intact endothelium, resulting in vasodilation. In the human heart, UII exhibits cardiac stimulant effects in vitro. In fish, UII exerts osmoregulatory functions, in particular epithelial ion transport across the isolated skin, intestine, urinary bladder, and gill. In the mammalian kidney, UII has vasodilator and natriuretic effects. UII may exert indirect actions on hydromineral homeostasis via the stimulation of prolactin and cortisol secretion. UII inhabits glucose-induced insulin release from the rat pancreas. In the central nervous system, UII exerts anxiogenic effects, hyperlocomotion, orexigenic and dipsogenic effects, and increased REM sleep duration.

Plasma UII concentration is elevated in renal failure, congestive heart failure, diabetes mellitus, and systemic and portal-hypertension caused by liver cirrhosis. In addition to the diseases mentioned above, UII is thought to play a central role in the pathogenesis of the metabolic syndrome, including obesity, hyperlipidemia, hypertension, hyperglycemia, and insulin resistance, leading to the development of type 2 diabetes, cardiovascular disease, nonalcoholic fatty liver disease, and renal impairment. UTR is expected in rat and human peripheral blood mononuclear cells, and UII acts as a chemoattractant for monocytes. UII activates the migration and differentiation of adventitial fibroblasts from the rat aorta. Thus, the UII system may be involved in the pathogenesis of atherosclerosis.

A neuropeptide isolated from the urophysis of teleost fish with a potent vasoconstrictor activity, urotensin II exerts behavioral effects and regulates cardiovascular, renal, and immune functions. Urotensin II (UII) was originally isolated from the urophysis of the goby fish (Gillichthys mirabilis) in 1980, on the basis of its ability to contract smooth muscles. A paralog, called the UII-related peptide (URP), was identified from the rat brain in 2003. UII has been identified in all vertebrate species, from lampreys to mammals. URP exists in tetrapods and teleosts, but has not been reported in other vertebrate classes. URP1 and URP2, a teleost counterpart of mammalian URP, have been characterized in teleosts. Both URP1 and URP2 are absent in tetrapods.