Urotensin II-related peptide, the endogenous ligand for the urotensin II receptor in the rat brain

Urotensin II (UII) is a piscine neuropeptide originally isolated from the teleost urophysis. The existence of UII in mammals has been demonstrated by cloning of the mammalian orthologs of UII precursor protein genes. While rat and mouse orthologs have been reported, only the tentative structures of UII peptides of these animals have been demonstrated, since prepro-UII proteins lack the typical processing sites in the amino-terminal region of the mature peptides. A novel peptide, UII-related peptide (URP), was discovered by monitoring UII-immunoreactivity in the rat brain, and its amino acid sequence was determined to be ACFWKYCV. cDNAs encoding rat, mouse, and human precursor proteins for URP were cloned and showed that the sequences of mouse and human URP peptides are identical to that for rat URP. URP was found to bind and activate the human or rat urotensin II receptors [GPR14, UT receptor (UTR)] and showed a hypotensive effect when administrated to anesthetized rats. The prepro-URP gene is expressed in several rat tissues, although with lower levels than the prepro-UII gene and, in the human, is expressed comparably to prepro-UII in several tissues except the spinal cord. These results suggest that URP is the endogenous and functional ligand for urotensin II receptor in the rat and mouse, and possibly in the human.     

Identification of urotensin II-related peptide as the urotensin II-immunoreactive molecule in the rat brain

Urotensin II (UII) has been reported as the most potent known vasoconstrictor. While rat and mouse orthologs of UII precursor protein have been reported, only the tentative structures of UII peptides of these animals have been demonstrated, since prepro-UII proteins lack typical processing sites for their mature peptides. In the present study, we isolated a novel peptide, UII-related peptide (URP), from the extract of the rat brain as the sole immunoreactive substance to anti-UII antibody; the amino acid sequence of the peptide was determined as ACFWKYCV. cDNAs encoding rat, mouse, and human precursor proteins for URP were cloned and revealed that the sequences of mouse and human URP peptides are the same as that for rat URP. Prepro-URP gene is expressed in several rat tissues such as those of the thymus, spleen, testis, and spinal cord, although with lower levels than the prepro-UII gene. In the human, the prepro-URP gene is expressed comparably to prepro-UII in several tissues except the spinal cord. URP was found to bind and activate the human or rat UII receptors (GPR14) and showed a hypotensive effect when administered to anesthetized rats. These results suggest that URP is the endogenous and functional ligand for UII receptor in the rat and mouse, and possibly in the human. We also describe the preparation of specific monoclonal antibodies raised against UII peptide and the establishment of a highly sensitive enzyme immunoassay system for UII peptides.     

Increased expression of urotensin II-related peptide and its receptor in kidney with hypertension or renal failure

Urotensin II-related peptide (URP) is a novel vasoactive peptide that shares urotensin II receptor (UT) with urotensin II. In order to clarify possible changes of URP expression in hypertension and chronic renal failure (CRF), the expressions of URP and UT were studied by quantitative RT-PCR and immunohistochemistry in kidneys obtained from spontaneous hypertensive rats (SHR), Wistar-Kyoto rats (WKY), and WKY with CRF due to 5/6 nephrectomy. Expression levels of URP mRNA and UT mRNA were significantly higher in the kidneys obtained from SHR compared with age-matched WKY (at 5-16 and 16 weeks old, respectively). A dissection study of the kidney into three portions (inner medulla, outer medulla and cortex) showed that the expression levels of URP mRNA and UT mRNA were highest in the inner medulla and the outer medulla, respectively, in both SHR and WKY. The expression levels of URP and UT mRNAs were greatly elevated in the remnant kidneys of CRF rats at day 56 after nephrectomy, compared with sham-operated rats (about 6.5- and 11.9-fold, respectively). Immunohistochemistry showed that URP immunostaining was found mainly in the renal tubules, vascular smooth muscle cells and vascular endothelial cells. UT immunoreactivity was localized in the renal tubules and vascular endothelial cells. These findings suggest that the expressions of URP and UT mRNAs in the kidney are enhanced in hypertension and CRF, and that URP and its receptor have important pathophysiological roles in these diseases.     

Urotensin II and urotensin II-related peptide (URP) in cardiac ischemia-reperfusion injury

Circulating urotensin II (UII) concentrations and the tissue expression of its cognate receptor (UT) are elevated in patients with cardiovascular disease (CVD). The functional significance of elevated plasma UII levels in CVD is unclear. Urotensin-related peptide (URP) is a paralog of UII in that it contains the six amino acid ring structures found in UII. Although both peptides are implicated as bioactive factors capable of modulating cardiovascular status, the role of both UII and URP in ischemic injury is unknown. Accordingly, we provide here the first report describing 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 30min preconditioning with either 1nM rUII or 10nM URP. Both rUII- and URP-induced significant vasodilation of coronary arteries before (both P<0.05) and after ischemia (both P<0.05). Rat UII alone lowered contractility prior to ischemia (P=0.053). Specific assay of perfusate revealed rUII and URP both significantly inhibited reperfusion myocardial creatine kinase (CK) release (P=0.012 and 0.036, respectively) and atrial natriuretic peptide (ANP) secretion (P=0.025). Antagonism of the UT receptor with 1muM 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, our data suggests 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 actions.     

Potent cardiovascular effects of homologous urotensin II (UII)-related peptide and UII in unanesthetized eels after peripheral and central injections

We cloned cDNAs encoding urotensin II (UII)-related peptide (URP) and UII in Japanese eel, Anguilla japonica, the former being the first such cloning in teleost fishes. Unlike the exclusive expression of UII in the urophysis, the URP gene was expressed most abundantly in the brain (medulla oblongata) followed by the urophysis. Peripheral injections of URP into eels increased blood pressure by 16.1 ± 0.8 mmHg at 0.1 nmol/kg in ventral aortic blood pressure (P(VA)) and with similar potency and efficacy to that of UII (relative potency of URP to UII = 0.83). URP/UII and ANG II preferentially acted on the branchial and systemic circulations, respectively, and the duration of effect was distinct among the three peptides in the order of UII (60 min) >URP (30 min) >ANG II (14 min) in P(VA). Urantide, a mammalian UII receptor antagonist, inhibited the URP effect (-63.6 ± 5.2%) to a greater extent than for UII (-39.9 ± 5.0%). URP and UII constricted isolated eel branchial and systemic arteries, showing their direct actions on the vascular smooth muscle. Central injection of URP increased blood pressure by 12.3 ± 0.8 mmHg at 50 pmol/eel in P(VA) and with similar efficacy but less potency (relative potency = 0.47) and shorter duration compared with UII. The central actions of URP/UII were more potent on the branchial circulation than on the systemic circulation, again opposite the effects of ANG II. The similar responses to peripheral and central injections suggest that peripheral hormones may act on the brain. Taken together, in eels, URP and UII are potent cardiovascular hormones like ANG II, acting directly on the peripheral vasculature, as well as a central vasomotor site, and their actions are mediated to different degrees by the UII receptor.     

Cardiovascular effects of native and non-native urotensin II and urotensin II-related peptide on rat and salmon hearts

Urotensin II (UII) was first discovered in the urophyses of goby fish and later identified in mammals, while urotensin II-related peptide (URP) was recently isolated from rat brain. We studied the effects of UII on isolated heart preparations of Chinook salmon and Sprague–Dawley rats. 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. Nω-nitro-_l-arginine methyl (l-NAME) and indomethacin significantly attenuated the URP and rat UII-induced vasodilation in the rat heart. We conclude that UII is a coronary vasodilator, an action that is species form specific. We also provide the first evidence for cardiac actions of URP, possibly via mechanisms common with UII.     

Urotensin II and urotensin II-related peptide activate somatostatin receptor subtypes 2 and 5

The UII and urotensin II-related peptide (URP) genes belong to the same superfamily as the somatostatin gene. It has been previously shown that somatostatin activates the UII-receptor (UTR). In contrast, the possible interaction between UII and URP and somatostatin receptors has remained scarcely analyzed. Herein, we have 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, our present data demonstrate that UII and URP directly activate sst2 and sst5 and thus mimic the effect of somatostatin on its cognate receptors.     

Effects of urotensin II on functional activity of late endothelial progenitor cells

Urotensin II (UII) is a potent vasoactive cyclic peptide which has multiple effects on the cardiovascular system. However, the effects of UII on late endothelial progenitor cells (EPCs) are still unclear. The aim of the present study is to investigate whether UII influences the functional activity of late EPCs. Late EPCs were isolated from human umbilical cord blood by Ficoll density gradient centrifugation and treated with UII (10(-10), 10(-9), 10(-8), 10(-7) and 10(-6)M), or vehicle control. Expression of urotensin II receptor (UT) in late EPCs was confirmed by indirect immunofluorescence staining. Late EPCs proliferation, migration and in vitro vasculogenesis activity were assayed with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, transwell chamber assay, and matrigel tube formation assay. Late EPCs adhesive assay was performed by replating cells on fibronectin-coated dishes, and then adherent cells were counted. Incubation with UII increased the migratory, adhesive and in vitro vasculogenesis capacity and inhibited the proliferative activity of late EPCs. Furthermore, these UII-mediated effects on late EPCs were attenuated by pretreatment with the UT antagonist urantide. These findings indicate that UII may exert multiple effects on functional activity of late EPCs through UT.     

Biochemical and functional characterization of high-affinity urotensin II receptors in rat cortical astrocytes

The urotensin II (UII) gene is primarily expressed in the central nervous system, but the functions of UII in the brain remain elusive. Here, we show that cultured rat astrocytes constitutively express the UII receptor (UT). Saturation and competition experiments performed with iodinated rat UII ([(125)I]rUII) revealed the presence of high- and low-affinity binding sites on astrocytes. Human UII (hUII) and the two highly active agonists hUII(4-11) and [3-iodo-Tyr9]hUII(4-11) were also very potent in displacing [(125)I]rUII from its binding sites, whereas the non-cyclic analogue [Ser5,10]hUII(4-11) and somatostatin-14 could only displace [(125)I]rUII binding at micromolar concentrations. Reciprocally, rUII failed to compete with [(125)I-Tyr0,D-Trp8]somatostatin-14 binding on astrocytes. Exposure of cultured astrocytes to rUII stimulated [(3)H]inositol incorporation and increased intracellular Ca(2+) concentration in a dose-dependent manner. The stimulatory effect of rUII on polyphosphoinositide turnover was abolished by the phospholipase C inhibitor U73122, but only reduced by 56% by pertussis toxin. The GTP analogue Gpp(NH)p caused its own biphasic displacement of [(125)I]rUII binding and provoked an affinity shift of the competition curve of rUII. Pertussis toxin shifted the competition curve towards a single lower affinity state. Taken together, these data demonstrate that rat astrocytes express high- and low-affinity UII binding sites coupled to G proteins, the high-affinity receptor exhibiting the same pharmacological and functional characteristics as UT.     

Liberation of urotensin II from the teleost urophysis: an historical overview

During the past 20 years, urotensin II (UII) has progressed from being a peptide synthesized only in the urophysis of the caudal neurosecretory system of teleost fish to being considered an important physiological regulator in mammals with implications for the pathogenesis of a range of human cardiovascular and renal diseases. The "liberation" of UII from the urophysis was a gradual process and involved the sequential realization that (a) UII is present not only in the urophysis but also in the central nervous systems (CNS) of teleosts, (b) UII peptides, similar in structure to the urophysial peptides, are present in the diffuse caudal neurosecretory systems and/or CNS of species less evolutionarily advanced than teleosts, including Agnatha, thereby showing that UII is a phylogenetically ancient peptide, (c) UII is present in the brain and spinal cord of a tetrapod, the green frog Rana ridibunda, and (d) the UII gene and its specific receptor (GPR14/UT) are expressed in the CNS and certain peripheral tissues of mammals, including the human. The discovery that the genomes of mammals contain an additional gene encoding a UII-related peptide (URP) and the availability of highly effective peptide and non-peptide antagonists to investigate the role of UII in human physiology and pathophysiology ensure that the peptide will remain "center stage" for several years to come.     

Increased gene expression of urotensin II-related peptide in the hearts of rats with congestive heart failure

Urotensin II-related peptide (URP) is a novel endogenous ligand for urotensin II receptor (UT-R). To investigate the pathophysiological role of URP in heart failure, we examined URP, UII and UT-R expression in hearts and kidneys of rats with congestive heart failure due to coronary ligation by quantitative RT-PCR and immunocytochemistry. Significantly increased expression levels of URP mRNA were found in the atrium, the right ventricle and the infarcted part of left ventricle of heart failure rats, when compared with sham-operated rats (about 2.2-fold, 2.7-fold and 3.9-fold, respectively). Expression levels of UII mRNA in the heart were about 10% of URP mRNA, and were slightly increased only in the infarcted part of left ventricle of heart failure rats, when compared with sham-operated rats. The expression levels of UT-R mRNA were increased in the atrium of heart failure rats. There was no significant change of URP, UII and UT-R mRNA expression levels in the kidney between heart failure and sham-operated rats. The myocardium was diffusely immunostained with URP in both rats. The blood vessels in the heart were positively immunostained with URP in heart failure rats, but not in sham-operated rats, whereas they were positively immunostained with UT-R in both rats. These findings suggest that the expression of URP, UII and UT-R is enhanced in failing heart, and the UII/URP/UT-R system has important pathophysiological roles in the progression of heart failure.     

Elevated expression of urotensin II and its receptor in diethylnitrosamine-mediated precancerous lesions in rat liver

Urotensin II (UII) is a somatostatin-like peptide involved in cell proliferation and in tumor biology. To explore the role of liver-derived UII in the pathogenesis of precancerous liver lesions in rat, we investigated the expression of UII and its receptor, UT, in diethylnitrosamine (DEN)-induced precancerous liver lesions and the effects of UII on cell proliferation by hepatic oval cells. Radioimmunoassay, RT-PCR, immunohistochemistry and western blot were used in this study. Compared with untreated controls, rats treated with DEN showed increased UII content by 47.7% in plasma and by 164.9% in liver tissue (all P < 0.01). The expression of UII protein and of both UT mRNA and protein was significantly enhanced in the liver of treated rats. Western blot analysis revealed that the expression of phosphorylated protein kinase C (p-PKC) and phosphorylated extracellular signal-regulated kinase (p-ERK1/2) was increased in the liver of treated animals. Treatment with UII (10⁻¹⁰-10⁻⁶ M) for 24 h significantly increased number of cultured hepatic oval cells (at 10⁻⁹-10⁻⁸ M). However, during the pre-incubation with calphostin C (inhibitor of PKC) or PD98059 (inhibitor of MEK), the proliferation was decreased by 40.1% and 25.4% respectively (both P < 0.05). In DEN-induced precancerous liver lesions, the UII/UT system was up-regulated, which may contribute to the pathogenesis of liver cancer through a PKC- or ERK1/2-dependent pro-mitogenic pathway in an autocrine/paracrine manner.     

Another ligand fishing for G protein-coupled receptor 14. Discovery of urotensin II-related peptide in the rat brain

Urotensin II (UII), which was originally isolated from the teleost urophysis, was identified as an endogenous ligand for orphan G protein-coupled receptor 14 (GPR14). The structure of mammalian UII was confirmed by isolation from spinal cord in porcine, or was easily predicted from the sequence of prepro-UII in human. For rat and mouse, however, only the tentative sequences of UII peptides have been demonstrated because the typical processing sites are absent from the amino-terminal region of the mature peptides. Isolation of UII-like immunoreactivity in rat brain revealed the presence of a novel peptide, designated urotensin II-related peptide (URP). URP binds and activates the human and rat urotensin II receptors (GPR14) and has a hypotensive effect when administrated to anesthetized rats. Based on the DNA sequences of the cloned prepro-URP gene, the amino acid sequences of mature URP for mouse and human are identical to that for rat URP. These results suggest that URP is the endogenous and functional ligand for urotensin II receptor in the rat and mouse, and possibly in the human.     

Comparative Distribution and In Vitro Activities of the Urotensin II-Related Peptides URP1 and URP2 in Zebrafish: Evidence for Their Colocalization in Spinal Cerebrospinal Fluid-Contacting Neurons

Urotensin II (UII) is an evolutionarily conserved neuropeptide initially isolated from teleost fish on the basis of its smooth muscle-contracting activity. Subsequent studies have demonstrated the occurrence of several UII-related peptides (URPs), such that the UII family is now known to include four paralogue genes called UII, URP, URP1 and URP2. These genes probably arose through the two rounds of whole genome duplication that occurred during early vertebrate evolution. URP has been identified both in tetrapods and teleosts. In contrast, URP1 and URP2 have only been observed in ray-finned and cartilaginous fishes, suggesting that both genes were lost in the tetrapod lineage. In the present study, the distribution of urp1 mRNA compared to urp2 mRNA is reported in the central nervous system of zebrafish. In the spinal cord, urp1 and urp2 mRNAs were mainly colocalized in the same cells. These cells were also shown to be GABAergic and express the gene encoding the polycystic kidney disease 2-like 1 (pkd2l1) channel, indicating that they likely correspond to cerebrospinal fluid-contacting neurons. In the hindbrain, urp1-expressing cells were found in the intermediate reticular formation and the glossopharyngeal-vagal motor nerve nuclei. We also showed that synthetic URP1 and URP2 were able to induce intracellular calcium mobilization in human UII receptor (hUT)-transfected CHO cells with similar potencies (pEC50=7.99 and 7.52, respectively) albeit at slightly lower potencies than human UII and mammalian URP (pEC50=9.44 and 8.61, respectively). The functional redundancy of URP1 and URP2 as well as the colocalization of their mRNAs in the spinal cord suggest the robustness of this peptidic system and its physiological importance in zebrafish.     

Comparative distribution of the mRNAs encoding urotensin I and urotensin II in zebrafish

The neural neurosecretory system of fishes produces two biologically active neuropeptides, i.e. the corticotropin-releasing hormone paralog urotensin I (UI) and the somatostatin-related peptide urotensin II (UII). In zebrafish, we have recently characterized two UII variants termed UIIalpha and UIIbeta. In the present study, we have investigated the distribution of UI, UIIalpha and UIIbeta mRNAs in different organs by quantitative RT-PCR analysis and the cellular localization of the three mRNAs in the spinal cord by in situ hybridization (ISH) histochemistry. The data show that the UI gene is mainly expressed in the caudal portion of the spinal cord and, to a lesser extent, in the brain, while the UIIalpha and the UIIbeta genes are exclusively expressed throughout the spinal cord. Single-ISH labeling revealed that UI, UIIalpha and UIIbeta mRNAs occur in large cells, called Dahlgren cells, located in the ventral part of the caudal spinal cord. Double-ISH staining showed that UI, UIIalpha and UIIbeta mRNAs occur mainly in distinct cells, even though a few cells were found to co-express the UI and UII genes. The differential expression of UI, UIIalpha and UIIbeta genes may contribute to the adaptation of Dahlgren cell activity during development and/or in various physiological conditions.     

Role of urotensin II in peripheral tissue as an autocrine/paracrine growth factor

Urotensin II (UII), originally isolated from goby urophysis, has been shown to be an endogenous ligand for an orphan G-protein-coupled receptor, GPR14. Recent development of PCR quantitative method revealed that UII and UT receptor (GPR14) were expressed in a broad range of tissues and organs, including cardiovascular and renal system, and assumed to function as an autocrine/paracrine factor. UII is a potent vasoconstrictor peptide, whose potency is greater than any other vasoconstrictors thus far known. However, its physiological roles have been found to extend far beyond the regulation of vascular tone. In this review, we focused on the mitogenic action of UII and discuss its underlying cellular mechanisms and potential physiological/pathophysiological role in various human diseases.     

Structure-activity relationships of urotensin II and URP

Urotensin II (U-II) and urotensin II-related peptide (URP) are the endogenous ligands for the orphan G-protein-coupled receptor GPR14 now renamed UT. At the periphery, U-II and/or URP exert a wide range of biological effects on cardiovascular tissues, airway smooth muscles, kidney and endocrine glands, while central administration of U-II elicits various behavioral and cardiovascular responses. There is also evidence that U-II and/or URP may be involved in a number of pathological conditions including heart failure, atherosclerosis, renal dysfunction and diabetes. Because of the potential involvement of the urotensinergic system in various physiopathological processes, there is need for the rational design of potent and selective ligands for the UT receptor. Structure-activity relationship studies have shown that the minimal sequence required to retain full biological activity is the conserved U-II(4-11) domain, in particular the Cys5 and Cys10 residues involved in the disulfide bridge, and the Phe6, Lys8 and Tyr9 residues. Free alpha-amino group and C-terminal COOH group are not necessary for the biological activity, and modifications of these radicals may even increase the stability of the analogs. Punctual substitution of native amino acids, notably Phe6 and Trp7, by particular residues generates analogs with antagonistic properties. These studies, which provide crucial information regarding the structural and conformational requirements for ligand-receptor interactions, will be of considerable importance for the design of novel UT ligands with increased selectivity, potency and stability, that may eventually lead to the development of innovative drugs.     

Orn5]URP acts as a pure antagonist of urotensinergic receptors in rat cortical astrocytes

Cultured rat astrocytes, which express functional urotensin II (UII)/UII-related peptide (URP) receptors (UT), represent a very suitable model to investigate the pharmacological profile of UII and URP analogs towards native UT. We have recently designed three URP analogs [D-Trp4]URP, [Orn5]URP and [D-Tyr6]URP, that act as UT antagonists in the rat aortic ring bioassay. However, it has been previously reported that UII/URP analogs capable of inhibiting the contractile activity of UII possess agonistic activity on UT-transfected cells. In the present study, we have compared the ability of URP analogs to compete for [125 I]URP binding and to modulate cytosolic calcium concentration ([Ca2+]c) in cultured rat astrocytes. All three analogs displaced radioligand binding: [D-Trp4]URP and [D-Tyr6]URP interacted with high- and low-affinity sites whereas [Orn5]URP only bound high-affinity sites. [D-Trp4]URP and [D-Tyr6]URP both induced a robust increase in [Ca2+]c in astrocytes while [Orn5]URP was totally devoid of activity. [Orn5]URP provoked a concentration-dependent inhibition of URP- and UII-evoked [Ca2+]c increase and a rightward shift of the URP and UII dose-response curves. The present data indicate that [D-Trp4]URP and [D-Tyr6]URP, which act as UII antagonists in the rat aortic ring assay, behave as agonists in the [Ca2+]c mobilization assay in cultured astrocytes, whereas [Orn5]URP is a pure selective antagonist in both rat aortic ring contraction and astrocyte [Ca2+]c mobilization assays.     

Identification of urotensin II as the endogenous ligand for the orphan G-protein-coupled receptor GPR14

Urotensin II (UII) is a neuropeptide with potent cardiovascular effects. Its sequence is strongly conserved among different species and has structural similarity to somatostatin. No receptor for UII has been molecularly identified from any species so far. GPR14 was cloned as an orphan G protein-coupled receptor with similarity to members of the somatostatin/opioid receptor family. We have now demonstrated that GPR14 is a high affinity receptor for UII and designate it UII-R1a. HEK293 cells and COS-7 cells transfected with rat GPR14 showed strong, dose-dependent calcium mobilization in response to fish, frog, and human UII. Radioligand binding analysis showed high affinity binding of UII to membrane preparations isolated from HEK293 cells stably expressing rat GPR14. In situ hybridization analysis showed that GPR14 was expressed in motor neurons of the spinal cord, smooth muscle cells of the bladder, and muscle cells of the heart. The identification of the first receptor for UII will allow better understanding of the physiological and pharmacological roles of UII.