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UT receptor

Family: Urotensin receptor

Contents:
Gene and Protein Information
Previous and Unofficial Names
Database Links
Agonists
Antagonists
Transduction Mechanisms
Tissue Distribution
Expression Datasets
Functional Assays
Physiological Functions
Physiological Consequences of Altering Gene Expression
Phenotypes, Alleles and Disease Models
General Comments
References
Gene and Protein Information
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 389 17q25.3 UTS2R urotensin 2 receptor 2
Mouse 7 386 11 E2 Uts2r urotensin 2 receptor 20
Rat 7 386 10q32.3 Uts2r urotensin 2 receptor 38,50
Previous and Unofficial Names
Names References
GPR14 2,38
UTR2
UTR
SENR (sensory epithelial neuropeptide-like receptor) 50
UII-R1
UR-II-R
UR2R
UT-II
SENR
UR-IIR
G protein-coupled receptor 14
UR-2-R
G-protein coupled receptor 14
G-protein coupled sensory epithelial neuropeptide-like receptor
putative G protein-coupled receptor (SENR)
putative G protein-coupled receptor (SENR) gene
urotensin 2 receptor
urotensin II receptor
urotensin-2 receptor
Database Links
ChEMBL Target 10927 (Hs), 10928 (Rn)
Ensembl ENSG00000181408 (Hs), ENSMUSG00000039321 (Mm), ENSRNOG00000036669 (Rn)
Entrez Gene 2837 (Hs), 217369 (Mm), 57305 (Rn)
GeneCards UTS2R (Hs)
GenitoUrinary Development Molecular Anatomy Project Uts2r (Mm)
Human Protein Reference Database 02938 (Hs)
InterPro Q9UKP6 (Hs), Q8VIH9 (Mm), P49684 (Rn)
KEGG Gene hsa:2837 (Hs), mmu:217369 (Mm), rno:57305 (Rn)
OMIM 600896 (Hs)
PharmGKB Gene PA28857 (Hs)
PhosphoSitePlus Q9UKP6 (Hs), Q8VIH9 (Mm), P49684 (Rn)
Protein Ontology (PRO) PRO:000001561 (Hs)
RefSeq Nucleotide NM_018949 (Hs), NM_145440 (Mm), NM_020537 (Rn)
RefSeq Protein NP_061822 (Hs), NP_663415 (Mm), NP_065412 (Rn)
TreeFam ENSG00000181408 (Hs), ENSMUSG00000039321 (Mm), ENSRNOG00000036669 (Rn)
UniGene Hs. 192720 (Hs)
UniProt Q9UKP6 (Hs), Q8VIH9 (Mm), P49684 (Rn)
Wikipedia UT receptor
Urotensin receptor
Search for 3D structures on the PDB
Search by keyword: Urotensin receptor UT receptor Search by accession number: P49684, Q9UKP6, Q8VIH9
Natural/Endogenous Ligand(s)
urotensin-II {Sp: Human} , urotensin-II {Sp: Mouse} , urotensin-II {Sp: Rat}
urotensin-related peptide {Sp: Human, Mouse, Rat}
Comments: aka GPR14
Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
[125I]U-II (human) Hs Full agonist 9.4 – 9.62 pKd 2,37
[125I]U-II (human) Mm Full agonist 9.2 pKd 20
[125I]U-II (human) Rn Full agonist 9.2 pKd 2
[Pen5]-U (4-11) (human) Hs Full agonist 9.7 pKi 24
U-II-(4-11) (human) Hs Full agonist 9.6 pKi 24
[Bz-Phe6]U-II (human) Hs Full agonist 9.1 pKi 7
urotensin-II {Sp: Mouse} Rn Full agonist 8.8 pKi 16
urotensin-II {Sp: Rat} Rn Full agonist 8.8 pKi 16
urotensin-II {Sp: Human} Rn Full agonist 8.7 pKi 16
urotensin-II {Sp: Human} Hs Full agonist 8.6 pKi 16,20,24
urotensin-II {Sp: Human} Mm Full agonist 8.2 – 9.0 pKi 16,20
urotensin-II {Sp: Rat} Mm Full agonist 8.6 pKi 16,20
urotensin-II {Sp: Mouse} Mm Full agonist 8.4 – 8.6 pKi 16,20
urotensin-II {Sp: Mouse} Hs Full agonist 8.5 pKi 16
urotensin-II {Sp: Rat} Hs Full agonist 8.5 pKi 16
AC-7954 Hs Full agonist 6.6 pKi 13,32
FL104 Hs Full agonist 5.8 – 7.5 pEC50 31,33
urotensin-related peptide {Sp: Human, Mouse, Rat} Hs Full agonist 8.6 pIC50 49
View species-specific agonist tables
Agonist Comments
Extensive SAR studies performed with U-II isopeptides emphasize the importance of the cyclic hexapeptide core of U-II [8,22,29-30]. Modifications of the exocyclic structure of U-II (e.g. amino terminus truncations, amidation) generally have only minor effects on UT affinity (consistent with the divergent amino-terminus/conservation of the carboxyl-octapeptide motif in U-II across species and the observation that human, goby, rat, mouse and pig U-II isopeptides are equipotent ligands at rodent and primate UT receptors). Indeed, hU-II(4-11) is typically ~3-fold more potent as a UT ligand compared to the parent peptide.

In contrast, disruption of the cyclic structure of U-II (e.g. [Ala5, 10], [Ser5,10], [Cys(Acm)5,10] analogs, D-Cys substitutions etc.) results in a profound loss in UT affinity [22,30]. [Cys5] substitution with penicillamine b,b-dimethylcysteine ([Pen5]hU-II(4-11)), however, stabilizes the cyclic structure of the truncated U-II analogue and is reported to enhance UT affinity ~3-fold [24].

Endocyclic modifications (e.g. D-substitutions, Ala-scan, single residue deletions) of Phe6, Trp7, Lys8 or Tyr9 have profound effects on ligand affinity for UT [8,22,29-30]. Such observations, coupled with pharmacophore modeling approaches (NMR studies, virtual compound bank screening), have lead to the identification of weak, nonpeptidic UT antagonists as described below e.g. S6716 [22]. Alternatively, weak, nonpeptide agonists (e.g. AC-7954) have also been identified using high throughput screening approaches [13].

[Bz-Phe6]hU-II (a high affinity, full agonist) has been used successfully as a photo-affinity label for rat UT where mutagenesis studies have demonstrated a ligand interaction with Met184/185 in TM4 of rat UT [7].

Several "nonselective" UT agonists have been identified. UT exhibits highest sequence homology (albeit ~27%) with somatostatin (SST4) receptors. Consequently, somatostatin analogues (SB-710411 and lanreotide, but not somatostatin itself) have been shown to be "nonselective" rodent and primate UT ligands [4,26]. Such an observation is interesting since these peptide analogues share some sequence homology with the conserved hexapeptide motif in the U-II isopeptide family, that required in U-II isopeptides for retention of UT receptor affinity. Similarly, BIM-23042, a neuromedin-B ligand, also shows a somewhat similar structure and also exhibits UT affinity [26]. Interestingly, however, such ligands are full agonists at human and monkey UT but are either partial agonists (murine UT) or antagonists (rat UT) at primate UT receptors (partial agonism may account, in part, for the functional antagonism seen with [Orn8]hU-II in the rat aorta [9]).

It is now recognized that the mammalian genome encodes for more than one "urotensin-II-like" peptide with the recent identification of URP, "urotensin-related peptide" (Ac[CFWKYC]V) by Sugo et al. (rat, mouse and human URP prepropeptides contain 113-119 amino acids; [49]]). Consistent with existing SAR data, this octapeptide fragment appears to exert similar pharmacodynamic actions as mature U-II. Preliminary inspection suggests that human URP is encoded on chromosome 3q29.
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
4-Cl-cinnamoyl-c[DCys-4Pal-DTrp-Orn-Val-Cys]-His-amide Hs Inverse agonist 8.4 pKd 12
tolyacetyl-c[DCys-Apa-DTrp-Orn-Val-Cys]-His-amide Hs Antagonist 7.7 pKd 12
BIM 23127 Hs Antagonist 6.7 pKd 25
urantide Hs Antagonist 8.3 pKi 42
SB-706375 Hs Antagonist 8.0 pKi 16
SB-706375 Rn Antagonist 7.7 pKi 16
SB-706375 Mm Antagonist 7.7 pKi 16
SB-436811 Rn Antagonist 6.7 pKi 28
SB-611812 Hs Antagonist 6.6 pKi 43
palosuran Hs Antagonist 7.1 pIC50 11
S6716 Hs Inverse agonist 6.4 pIC50 22
View species-specific antagonist tables
Antagonist Comments

Following detailed SAR studies using a variety of U-II analogues [8,22,29-30], several groups have focused on modifying the cyclic hexapeptide core of the U-II isopeptide family in an attempt to generate UT antagonists. In addition, several somatostatin derivatives were modified to generate weak, non-selective functional UT receptor antagonists such as SB-710411 [4] and PRL-2903 [44].

Recently, significant improvements in both UT receptor potency and selectivity have been made in such somatostatin derivatives following Lys/Orn subsitutions (as was seen in [Orn8]hU-II [9]) and by placing various arylacylating groups on the amino-terminus of the peptide ring e.g. 4-Cl-cinnamoyl-c[DCys-4Pal-DTrp-Orn-Val-Cys]-His-amide is a 4nM ligand and human and rat UT whereas tolylacetyl-c[DCys-Apa-DTrp-Orn-Val-Cys]-His-amide appears to exhibit selectivity for the rat UT receptor (19nM) over the human homologue (246nM) [12]. Little is known, however, about the selectivity of these ligands against other G-protein-coupled receptors.

Although BIM-23127 is a neuromedin-B ligand and, therefore, not considered to be "selective" as a U-II antagonist, it is a relatively potent ligand at rat UT and human UT (20-30nM pA2 against hU-II-induced Ca2+-mobilization) [25].

Using an NMR-based/virtual screening approach, S6716 has been identified as a weak UT receptor antagonist with an IC50 of ~400nM [22]. Indeed, several publications are beginning to appear in the patent literature claiming the identification of potent, selective nonpeptidic antagonists [14-15,17]. However, as for the indole derivative S6716, to date, little detailed pharmacological information is available on such moieties such as selectivity, nature of antagonism (competitive versus insurmountable), rodent versus primate UT receptor affinities etc. [14-15,17].

Urantide, [Pen5,DTrp7,Orn8]hU-II(4-11), is a recently described potent and selective peptidic UT receptor antagonist (high affinity ligand with a pKi8.3). Urantide blocks hU-II-induced contractions in the rat aorta without altering those induced by noradrenaline or endothelin-1 [42]. Although functional antagonism has been demonstrated at the rat UT, its should be noted that, to date, no such property has been ascribed for urantide at the primate receptor i.e. urantide is a potent human UT ligand but functional characterization e.g. inhibition of Ca2+-mobilization) has not been performed. As such, a lack of intrinsic activity remains to be established at the primate UT receptor and caution should be used when evaluating urantide in human and monkey systems (poor receptor density/signal transduction coupling in recombinant cell based assay systems can make partial agonists with low intrinsic activity erreneosuly appear to behave as antagonists [9]).
Primary Transduction Mechanisms
Transducer Effector/Response
Gq/G11 family Phospholipase C stimulation
Comments:  To date, relatively little research has focusd on urotensin-II signaling and specific G-protein-coupling pathways. Signaling events are associated with phospholipase C-mediated increases in [Ca2+] consistent with Gq/G11 coupling [36]. Indeed, urotensin-II/LDL-induced vascular smooth muscle proliferation is inhibited in part by inhibition of Gq (with anti-Gq/G11α antibodies, although the inhibition was of the synergistic actions of urotensin-II with LDL and not urotensin-II alone [53]). In similar assays, inhibition of Gαq (dominant negative antisense delivered by adenovirus) attenuates urotensin-II-mediated cardiac myocyte hypertrophy in vitro (although, notably, inhibition was only partial [52]). Such data is of interest since it has been observed that urotensin-II-mediated signal transduction (ERK-activation) is also sensitive to pertussis toxin, albeit in recombinant CHO cells expressing human UT (suggestive of a role for Gi/o [56]). In intact tissues such as the rabbit isolated aorta, U-II-mediated vasoconstriction is associated with phospholipase-C mediated Ca2+/inositol signaling in accord with cell based assays depicting a major role for Gq in mediating the cellular actions of urotensin-II [46]. Such activity is also coupled to protein kinase C [44], [53] although this may differ in rat spinal neurons where [Ca2+]-mobilization is associated with protein kinase-A activation [21]).
References:  36,46,52-53,56
Tissue Distribution
Multiple approaches have demonstrated that human UT expression is relatively ubiquitous with mRNA and protein being documented in (but not limited to) heart (cardiomyocytes, fibroblasts), arteries (endothelium, vascular smooth muscle, atheroma), kidney, skeletal muscle and CNS.
Species:  Human
Technique:  PCR, Northern blot analysis, radioligand binding
References:  2,20,37
Murine UT cDNA transcripts (PCR) are present within cardiac and vascular (thoracic but not abdominal aorta) tissue in addition to bladder and pancreas. Trace levels of expression are also observed in skeletal muscle, oesophagus, lung and adipose tissue.
Species:  Mouse
Technique:  PCR.
References:  2,19-20,38,50
A similar pattern of expression to that of the mouse is seen within major cardiovascular tissue along with the CNS and sensory epithelia, spleen, kidney, ovary, lung and liver.
Species:  Rat
Technique:  PCR.
References:  2,19-20,38,50
Expression Datasets

Click here to show/hide data

Log average relative transcript abundance in mouse tissues measured by qPCR from Regard, J.B., Sato, I.T., and Coughlin, S.R. (2008). Anatomical profiling of G protein-coupled receptor expression. Cell, 135(3): 561-71. [PMID:18984166] [Raw data: website]

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Functional Assays
Intracellular [Ca2+]i - levels elevated in response to exogenous U-II in intact HEK 293 cells.
Species:  Mouse
Tissue:  HEK 293 cells expressing recombinant UT receptors.
Response measured:  Intracellular Ca2+ concentrations measured by fluorescence of fura-2/AM
References:  20,35,40-41
U-II stimulated in time- and dose-dependent manners, the phosphorylation level of ERK. Urotensin II-induced proliferation of VSMCs was inhibited by ERK kinase inhibitor PD98059
Species:  Rat
Tissue:  Cultured vascular smooth muscle cells (VSMC) from adult rat aorta
Response measured:  Extracellular signal-regulated kinase (ERK) activation
References:  51
Recombinant cell-based functional assays: intracellular signal transduction
Species:  Human
Tissue:  Recombinant HEK-293 cells
Response measured:  Intracellular signal transduction e.g. [Ca2+]-mobilization
References:  2
ERK activation in transfected CHO cells
Species:  Human
Tissue:  CHO cells expressing cloned receptor
Response measured:  Activation of extracellular signal-regulated kinase 1/2 (ERK1/2)
References:  56
U-II induced [Ca2+]i increases in spinal cord neurons with a threshold of 10-9M, and a maximal effect at 10-6
Species:  Rat
Tissue:  Dissociated cultures of spinal cord neurons from newborn rats
Response measured:  Intracellular Ca2+ concentrations measured by fluorescence of fura 2-AM
References:  21
U-II dose depenantly activated ERKs and induced expression of specific genes encoding atrial natriuretic peptide and brain natriuretic peptide. This significantly incresed amino acid incorporation into proteins and increased cell size and myofibril organisation.
Species:  Rat
Tissue:  Cultured cardiomyocytes from neonatal rats
Response measured:  Extracellular signal-regulated kinase (ERK) activation
References:  57
U-II induced smooth muscle contraction was inhibited by the Rho-kinase inhibitor Y-27632 and by a membrane-permeant RhoA inhibitor (TAT-C3).
Species:  Rat
Tissue:  Endothelium-denuded rings of adult rat aorta
Response measured:  Smooth muscle contraction
References:  47
Physiological Functions
Vasoconstriction.
Species:  Rat
Tissue:  Isolated aortic ring contraction.
References:  2,19
Attenuation of glucose-stimulated insulin secretion.
Species:  Rat
Tissue:  Isolated perfused pancreas.
References:  48
Cardiac contractility.
Species:  Human
Tissue:  Isolated right atrial trabeculae.
References:  45
Regulation of locomotor function.
Species:  Mouse
Tissue:  In vivo.
References:  10
Enhancement of REM (rapid eye movement) sleep and wakefulness.
Species:  Rat
Tissue:  In vivo.
References:  27
Physiological Consequences of Altering Gene Expression
Adenovirus-mediated up-regulation of rat recombinant UT expression in neonatal cardiomyocytes results in significant urotensin-II-dependent activation of hypertrophic signaling (increased total protein content).
Species:  Rat
Tissue: 
Technique:  Retroviral infection
References:  52
Selective attenuation of vasoconstrictor phenotype to urotensin-II in UT knockout mice
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  3
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Uts2rtm1Djbe Uts2rtm1Djbe/Uts2rtm1Djbe
B6.129P2-Uts2r		 MGI:2183450  MP:0000250 abnormal vasoconstriction PMID: 12770952 
General Comments
In addition to human, rat and mouse UT, full-length primate UT has been cloned (389 amino acid residues, Accession number Q8HYC3) [20]. In addition, SwissProt contains an entry for a (partial) bovine UT sequence (Accession number P49220).

The detailed pharmacological characterization of many of the assays described herein is somewhat limited currently due to a lack of suitable, well characterized tools compounds. However, this is likely to change in the near future due significant advances made recently with respect to the development of peptidic and small molecule agonists and antagonists for UT (see [4,7-9,13,22,24,26,29-30], [14,17]).

The response of humans to systemic U-II administration is somewhat ambiguous [15,17]. Whereas Bohm & Pernow [6] reported that brachial artery infusion of U-II dose-dependently reduced forearm blood flow in normal human volunteers, Webb and colleagues [1,55] unable to observe a similar phenomenon in man using strikingly similar methodologies. Notably, Lim et al. [34] have recently compared the effect of iontophoresed U-II on skin microvascular tone in normal subjects and patients with congestive heart failure. Using laser Doppler velocimetry, this group report dose-dependent U-II mediated vasodilation in normal subjects. This contrasts with the vasoconstrictor response seen in patients with heart failure.

Recently, it has been suggested that the potential pathophysiological actions of U-II extend beyond the cardiovascular system to encompass metabolic diseases (for recent reviews see [17,23]). Indeed, a recent report Wenyi et al. [54] have proposed a role for U-II in the control of insulin sensitivity and the development of diabetes mellitus based on a pharmacogenomic study which examined the presence of a single nucleotide polymorphism in the human preproU-II gene, specifically S89N (chromosome 1p36-p32 is proposed as being linked to Type 2 diabetes in Japanese subjects).

In addition to renal epithelia (procine LLCPK1 cells [39]) and rat neurons ( dissociated spinal cord neurons [21]), native U-II binding sites/functional receptors have recently been described in two human skeletal muscle cells lines (the rhabdomyosarcoma cell lines SJRH30 and TE-671 [5,18]).

REFERENCES

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1. Affolter, J. T., Newby, D. E., Wilkinson, I. B., Winter, M. J., Balment, R. J. and Webb, D. J. (2002) No effect on central or peripheral blood pressure of systemic urotensin II infusion in humans. Br. J. Clin. Pharmacol., 54: 617-621. [PMID:12492609]

2. Ames, R. S., Sarau, H. M., Chambers, J. K., Willette, R. N., Aiyar, N. V., Romanic, A. M., Louden, C. S., Foley, J. J., Sauermelch, C. F., Coatney, R. W., Ao, Z., Disa, J., Holmes, S. D., Stadel, J. M., Martin, J. D., Liu, W. S., Glover, G. I., Wilson, S., McNulty, D. E., Ellis, C. E., Elshourbagy, N. A., Shabon, U., Trill, J. J., Hay, D. W., Douglas, S. A. et al.. (1999) Human urotensin-II is a potent vasoconstrictor and agonist for the orphan receptor GPR14. Nature, 401: 282-286. [PMID:10499587]

3. Behm, D. J., Harrison, S. M., Ao, Z., Maniscalco, K., Pickering, S. J., Grau, E. V., Woods, T. N., Coatney, R. W., Doe, C. P., Willette, R. N., Johns, D. G. and Douglas, S. A. (2003) Deletion of the UT receptor gene results in the selective loss of urotensin-II contractile activity in aortae isolated from UT receptor knockout mice. Br. J. Pharmacol., 139: 464-472. [PMID:12770952]

4. Behm, D. J., Herold, C. L., Ohlstein, E. H., Knight, S. D., Dhanak, D. and Douglas, S. A. (2002) Pharmacological characterization of SB-710411 (Cpa-c[D-Cys-Pal-D-Trp-Lys-Val-Cys]-Cpa-amide), a novel peptidic urotensin-II receptor antagonist. Br. J. Pharmacol., 137: 449-458. [PMID:12359626]

5. Birker-Robaczewska, M., Boukhadra, C., Studer, R., Mueller, C., Binkert, C. and Nayler, O. (2003) The expression of urotensin II receptor (U2R) is up-regulated by interferon-gamma. J. Recept. Signal. Transduct. Res., 23: 289-305. [PMID:14753294]

6. Bohm, F. and Pernow, J. (2002) Urotensin II evokes potent vasoconstriction in humans in vivo. Br. J. Pharmacol., 135: 25-27. [PMID:11786476]

7. Boucard, A. A., Sauve, S. S., Guillemette, G., Escher, E. and Leduc, R. (2003) Photolabelling the rat urotensin II/GPR14 receptor identifies a ligand-binding site in the fourth transmembrane domain. Biochem J., 370: 829-838. [PMID:12495432]

8. Brkovic, A., Hattenberger, A., Kostenis, E., Klabunde, T., Flohr, S., Kurz, M., Bourgault, S. and Fournier, A. (2003) Functional and binding characterizations of urotensin II-related peptides in human and rat urotensin II-receptor assay. J. Pharmacol. Expl Ther., 306: 1200-1209. [PMID:12807997]

9. Camarda, V., Guerrini, R., Kostenis, E., Rizzi, A., Calo, G., Hattenberger, A., Zucchini, M., Salvadori, S. and Regoli, D. (2002) A new ligand for the urotensin II receptor. Br. J. Pharmacol., 137: 311-314. [PMID:12237249]

10. Clark, S. D., Nothacker, H. P., Blaha, C. D., Tyler, C. J., Duangdao, D. M., Grupke, S. L., Helton, D. R., Leonard, C. S. and Civelli, O. (2005) Urotensin II acts as a modulator of mesopontine cholinergic neurons. Brain Res, : -. [PMID:16183039]

11. Clozel, M; Binkert, C; Birker-Robaczewska, M; Boukhadra, C; Ding, SS; Fischli, W; Hess, P; Mathys, B; Morrison, K; Müller, C; et al.. (2004) Pharmacology of the urotensin-II receptor antagonist palosuran (ACT-058362; 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea sulfate salt): first demonstration of a pathophysiological role of the urotensin System. J. Pharmacol. Exp. Ther., 311 (1): 204-12. [PMID:15146030]

12. Coy, D. H., Rossowski, W. J., Cheng, B. L. and Taylor, J. E. (2003) Structural requirements at the N-terminus of urotensin II octapeptides. Peptides., 23: 2259-2264. [PMID:12535707]

13. Croston, G. E., Olsson, R., Currier, E. A., Burstein, E. S., Weiner, D., Nash, N., Severance, D., Allenmark, S. G., Thunberg, L., Ma, J. N., Mohell, N., O'Dowd, B., Brann, M.R. and Hacksell, U. (2002) Discovery of the first nonpeptide agonist of the GPR14/urotensin-II receptor: 3-(4-chlorophenyl)-3-(2- (dimethylamino)ethyl)isochroman-1-one (AC-7954). J. Med. Chem., 45: 4950-4953. [PMID:12408704]

14. Dhanak, D., Neeb, M. J. and Douglas, S. A. (2003) Urotensin-II receptor modulators. Ann. Rep. Med. Chem., 38: 99-110.

15. Douglas, S. A. (2003) Human urotensin-II as a novel cardiovascular target: "heart" of the matter or simply a fishy "tail". Curr. Opin. Pharmacol., 3: 159-167. [PMID:12625888]

16. Douglas, S. A., Behm, D. J., Aiyar, N. V., Naselsky, D., Disa, J., Brooks, D. P., Ohlstein, E. H., Gleason, J. G., Sarau, H. M., Foley, J. J., Buckley, P. T., Schmidt, D. B., Wixted, W. E., Widdowson, K., Riley, G., Jin, J., Gallagher, T. F., Schmidt, S. J., Ridgers, L., Christmann, L. T., Keenan, R. M., Knight, S. D. and Dhanak, D. (2005) Nonpeptidic urotensin-II receptor antagonists I: in vitro pharmacological characterization of SB-706375. Br J Pharmacol, 145: 620-635. [PMID:15852036]

17. Douglas, S. A., Dhanak, D. and Johns, D. J. (2003) From "gills to pills": urotensin-II as a regulator of mammalian cardiorenal function. Trends Pharmacol. Sci., 25: 76-85. [PMID:15102493]

18. Douglas, S. A., Naselsky, D., Ao, Z., Disa, J., Herold, C. L., Lynch, F. and Aiyar, N. V. (2004) Identification and pharmacological characterization of native, functional human urotensin-II receptors in rhabdomyosarcoma cell lines. Br J Pharmacol., --: -----. [PMID:15210573]

19. Douglas, S. A., Sulpizio, A. C., Piercy, V., Sarau, H. M., Ames, R. S., Aiyar, N. V., Ohlstein, E. H. and Willette, R. N. (2000) Differential vasoconstrictor activity of human urotensin-II in vascular tissue isolated from the rat, mouse, dog, pig, marmoset and cynomogus monkey. Br. J. Pharmacol., 131: 1262-1274. [PMID:11090097]

20. Elshourbagy, N. A., Douglas, S. A., Shabon, U., Harrison, S., Duddy, G., Sechler, J. L., Ao, Z., Maleeff, B. E., Naselsky, D., Disa, J. and Aiyar, N.V. (2002) Molecular and pharmacological characterization of genes encoding urotensin-II peptides and their cognate G-protein-coupled receptors from the mouse and monkey. Br. J. Pharmacol., 136: 9-22. [PMID:11976263]

21. Filipeanu, C. M., Brailoiu, E., Le Dun, S. and Dun, N. J. (2002) Urotensin-II regulates intracellular calcium in dissociated rat spinal cord neurons. J. Neurochem., 83: 879-884. [PMID:12421360]

22. Flohr, S., Kurz, M., Kostenis, E., Brkovich, A., Fournier, A. and Klabunde, T. (2002) Identification of nonpeptidic urotensin II receptor antagonists by virtual screening based on a pharmacophore model derived from structure-activity relationships and nuclear magnetic resonance studies on urotensin II. J. Med. Chem., 45: 1799-1805. [PMID:11960491]

23. Gilbert, R. E., Douglas, S. A. and Krum, H. (2004) Urotensin as a novel therapeutic target for the clinical management of cardiorenal disease. Curr. Opin. Invest. Drugs, 5: 276-282. [PMID:15083593]

24. Grieco, P., Carotenuto, A., Campiglia, P., Zampelli, E., Patacchini, R., Maggi, C.A., Novellino, E. and Rovero, P. (2002) A new, potent urotensin II receptor peptide agonist containing a Pen residue at the disulfide bridge. J. Med. Chem., 45: 4391-4394. [PMID:12238917]

25. Herold, C. L., Behm, D. J., Buckley, P. T., Foley, J. J., Wixted, W. E., Sarau, H. M. and Douglas, S. A. (2003) The neuromedin B receptor antagonist, BIM-23127, is a potent antagonist at human and rat urotensin-II receptors. Br. J. Pharmacol., 139: 203-207. [PMID:12770925]

26. Herold, C. L., Behm, D. J., Buckley, P. T., Foley. J. J., null and Douglas, S. A. (2002) The peptidic somatostatin analogs lanreotide, BIM-23127 and BIM 23042 are urotensin-II receptor ligands. Pharmacologist, 44: 170-171.

27. Huitron-Resendiz, S., Kristensen, M. P., Sanchez-Alavez, M., Clark, S. D., Grupke, S. L., Tyler, C., Suzuki, C., Nothacker, H. P., Civelli, O., Criado, J. R., Henriksen, S. J., Leonard, C. S. and De Lecea, L. (2005) Urotensin II modulates rapid eye movement sleep through activation of brainstem cholinergic neurons. J Neurosci, 25: 5465-6474. [PMID:15944374]

28. Jin, J., Dhanak, D., Knight, S. D., Widdowson, K., Aiyar, N., Naselsky, D., Sarau, H. M., Foley, J. J., Schmidt, D. B., Bennett, C. D., Wang, B., Warren, G. L., Moore, M. L., Keenan, R. M., Rivero, R. A. and Douglas, S. A. (2005) Aminoalkoxybenzyl pyrrolidines as novel human urotensin-II receptor antagonists. Bioorg Med Chem Lett, 15: 3229-3232. [PMID:15936190]

29. Kinney, W. A., Almond, H. R. Jr., Qi, J., Smith, C. E., Santulli, R. J., de Garavilla, L., Andrade-Gordon, P., Cho, D. S., Everson, A. M., Feinstein, M. A., Leung, P. A. and Maryanoff, B. E. (2002) Structure-function analysis of urotensin II and its use in the construction of a ligand-receptor working model. Angew. Chem. Int. Ed. Engl., 41: 2940-2944. [PMID:12203418]

30. Labarrere, P., Chatenet, D., Leprince, J., Marionneau, C., Loirand, G., Tonon, M.-C., Dubesy, C., Scalbert, E., Pfeiffer, B., Renard, P., Calas, B., Pacaud, P. and Vaudry, H. (2003) Structure-activity relationships of human urotensin II and related analogues on rat aortic contraction. J. Enz. Inhib. Med. Chem., 18: 77-88. [PMID:12943190]

31. Lehmann, F; Currier, EA; Clemons, B; Hansen, LK; Olsson, R; Hacksell, U; Luthman, K. (2009) Novel and potent small-molecule urotensin II receptor agonists. Bioorg. Med. Chem., 17 (13): 4657-65. [PMID:19481466]

32. Lehmann, F; Currier, EA; Olsson, R; Hacksell, U; Luthman, K. (2005) Isochromanone-based urotensin-II receptor agonists. Bioorg. Med. Chem., 13 (8): 3057-68. [PMID:15781415]

33. Lehmann, F; Lake, L; Currier, EA; Olsson, R; Hacksell, U; Luthman, K. (2007) Design, parallel synthesis and SAR of novel urotensin II receptor agonists. Eur J Med Chem, 42 (2): 276-85. [PMID:17112638]

34. Lim, M., Honisett, S., Sparkes, C. D., Komesaroff, P., Kompa, A. and Krum, H. (2004) Differential effect of urotensin II on vascular tone in normal subjects and patients with chronic heart failure. Circulation, 109: 1212-1214. [PMID:15007012]

35. Liu, Q., Pong, S. S., Zeng, Z., Zhang, Q., Howard, A. D., Williams, D. L. Jr., Davidoff, M., Wang, R., Austin, C. P., McDonald, T. P., Bai, C., George, S. R., Evans, J. F. and Caskey, C. T. (1999) Identification of urotensin II as the endogenous ligand for the orphan G-protein-coupled receptor GPR14. Biochem. Biophys. Res. Commun., 266: 174-178. [PMID:10581185]

36. Maguire, J. J. and Davenport, A. P. (2002) Is urotensin-II the new endothelin?. Br. J. Pharmacol., 137: 579-588. [PMID:12381671]

37. Maguire, J. J., Kuc, R. E. and Davenport, A. P. (2000) Orphan-receptor ligand human urotensin II: receptor localization in human tissues and comparison of vasoconstrictor responses with endothelin-1. Br. J. Pharmacol., 131: 441-446. [PMID:11015293]

38. Marchese, A., Heiber, M., Nguyen, T., Heng, H. H., Saldivia, V. R., Cheng, R., Murphy, P. M., Tsui, L. C., Shi, X., Gregor, P. et al.. (1995) Cloning and chromosomal mapping of three novel genes, GPR9, GPR10, and GPR14, encoding receptors related to interleukin 8, neuropeptide Y, and somatostatin receptors. Genomics, 29: 335-344. [PMID:8666380]

39. Matsushita, M., Shichiri, M., Fukai, N., Ozawa, N., Yoshimoto, T., Takasu, N. and Hirta, Y. (2003) Urotensin II is an autocrine/paracrine growth factor for the porcine renal epthelial cell line, LLCPK1. Endocrinol., 144: 1825-1831. [PMID:12697688]

40. Mori, M., Sugo, T., Abe, M., Shimomura, Y., Kurihara, M., Kitada, C., Kikuchi, K., Shintani, Y., Kurokawa, T., Onda, H., Nishimura, O. and Fujino, M. (1999) Urotensin II is the endogenous ligand of a G-protein-coupled orphan receptor, SENR (GPR14). Biochem. Biophys. Res. Commun., 265: 123-129. [PMID:10548501]

41. Nothacker, H.-P., Wang, Z., McNeill, A. M., Saito, Y., Merten, S., O'Dowd, B., Duckles, S. P. and Civelli, O. (1999) Identification of the natural ligand of an orphan G-protein-coupled receptor involved in the regulation of vasoconstriction. Nat. Cell Biol., 1: 383-385. [PMID:10559967]

42. Patacchini, R., Santicioli, P., Giuliani, S., Grieco, P., Novellino, E., Rovero, P. and Maggi, C.A. (2003) Urantide, an ultrapotent urotensin II antagonist peptide in the rat aorta. Br. J. Pharmacol., 140: 1155-1158. [PMID:14645137]

43. Rakowski, E; Hassan, GS; Dhanak, D; Ohlstein, EH; Douglas, SA; Giaid, A. (2005) A role for urotensin II in restenosis following balloon angioplasty: use of a selective UT receptor blocker. J. Mol. Cell. Cardiol., 39 (5): 785-91. [PMID:16171813]

44. Rossowski, W. J., Cheng, B. L., Taylor, J. E., Datta, R. and Coy, D. H. (2002) Human urotensin II-induced aorta ring contractions are mediated by protein kinase C, tyrosine kinases and Rho-kinase: inhibition by somatostatin receptor antagonists. Eur. J. Pharmacol., 438: 159-170. [PMID:11909607]

45. Russell, F. D., Molenaar, P. and O'Brien, D. M. (2001) Cardiostimulant effects of urotensin-II in human heart in vitro. Br. J. Pharmacol., 132: 5-9. [PMID:11156554]

46. Saetrum Opgaard, O., Nothacker, H., Ehlert, F. J. and Krause, D. N. (2000) Human urotensin II mediates vasoconstriction via an increase in inositol phosphates. Eur. J. Pharmacol., 406: 265-271. [PMID:11020490]

47. Sauzeau, V., Le Mellionnec, E., Betoglio, J., Scalbert, E., Pacaud, P and Loirand, G. (2001) Human urotensin II-induced contraction and arterial smooth muscle cell proliferation are mediated by RhoA and Rho-kinase. Circ. Res., 88: 1102-1104. [PMID:11397774]

48. Silvestre, R. A., Rodriguez-Gallardo, J., Egido, E. M. and Marco, J. (2001) Inhibition of insulin release by urotensin II: a study on the perfused rat pancreas. . Horm. Metab. Res., 33: 379-381. [PMID:11383923]

49. Sugo, T., Murakami, Y., Shimomura, Y., Harada, M., Abe, M., Ishibashi, Y., Kitada, C., Miyajima, N., Suzuki, N., Mori, M. and Fujino, M. (2003) Identification of urotensin II-related peptide as the urotensin II-immunoreactive molecule in the rat brain. Biochem. Biophys. Res. Commun., 310: 860-868. [PMID:14550283]

50. Tal, M., Ammar, D. A., Karpuj, M., Krizhanovsky, V., Naim, M. and Thompson, D. A. (1995) A novel putative neuropeptide receptor expressed in neural tissue, including sensory epithelia. Biochem. Biophys. Res. Commun., 209: 752-759. [PMID:7733947]

51. Tamura, K., Okazaki, M., Tamura, M., Isozumi, K., Tasaki, H. and Nakashima, Y. (2003) Urotensin II-induced activation of extracellular signal-regulated kinase in cultured vascular smooth muscle cells: involvement of cell adhesion-mediated integrin signaling. Life Sci., 72: 1049-1060. [PMID:12495783]

52. Tzanidis, A., Hannan, R. D., Thomas, W. G., Onan, D., Autelitano, D. J., See, F., Kelly, D. J., Gilbert, R. E. and Krum, H. (2003) Direct actions of urotensin II on the heart: implications for cardiac fibrosis and hypertrophy. Circ. Res., 93: 246-253. [PMID:12842917]

53. Watanabe, T., Pakala, R., Katagiri, T. and Benedict, C.R. (2001) Synergistic effect of urotensin II with mildly oxidized LDL on DNA synthesis in vascular smooth muscle cells. Circulation, 104: 16-18. [PMID:11435331]

54. Wenyi, Z., Suzuki, S., Hirai, M., Hinokio, Y., Tanizawa, Y., Matsutani, A., Satoh, J. and Oka, Y. (2003) Role of urotensin II gene in genetic susceptibility to Type 2 diabetes mellitus in Japanese subjects. Diabetologia, 46: 972-976. [PMID:12830381]

55. Wilkinson, I.B., Affolter, J. T., de Haas, S. L., Pellegrini, M. P., Boyd, J., Winter, M. J., Balment, R. J. and Webb, D. J. (2001) High plasma concentrations of human urotensin II do not alter local or systemic hemodynamics in man. Cardiovasc. Res., 53: 341-347. [PMID:11827684]

56. Ziltener, P., Mueller, C., Haenig, B., Scherz, M. W. and Nayler, O. (2002) Urotensin II mediates ERK1/2 phosphorylation and proliferation in GPR14-transfected cell lines. J. Recept. Signal Transduct. Res., 22: 155-168. [PMID:12503613]

57. Zou, Y., Nagai, R. and Yamazaki, T. (2001) Urotensin II induces hypertrophic responses in cultured cardiomyocytes from neonatal rats. FEBS Lett., 508: 57-60. [PMID:11707268]

To cite this database page, please use the following:

Stephen A. Douglas, Margaret R. MacLean, Eliot H. Ohlstein, Walter G. Thomas, Hubert Vaudry, David J. Webb.
Urotensin receptor: UT receptor. Last modified on 15/02/2013. Accessed on 21/05/2013. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=365.


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