更新于：2024-09-19

UTS2R

更新于：2024-09-19

基本信息

别名

G protein-coupled receptor 14、G-protein coupled receptor 14、GPR14

+ [6]

简介

High affinity receptor for urotensin-2 and urotensin-2B. The activity of this receptor is mediated by a G-protein that activate a phosphatidylinositol-calcium second messenger system.

关联

项与 UTS2R 相关的药物

GSK1562590

靶点

UTS2R

作用机制

UTS2R拮抗剂

在研机构

GlaxoSmithKline, Inc.

原研机构

GlaxoSmithKline, Inc.

在研适应症

心血管疾病

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

UPG-111

靶点

UTS2R

作用机制

UTS2R 负变构调节剂

在研机构

Università degli Studi di Napoli Federico II

原研机构

Università degli Studi di Napoli Federico II

在研适应症-

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

UPG-109

靶点

UTS2R

作用机制

UTS2R 负变构调节剂

在研机构

Università degli Studi di Napoli Federico II

原研机构

Università degli Studi di Napoli Federico II

在研适应症-

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

项与 UTS2R 相关的临床试验

NCT01424280 / Completed临床1期

A Phase 1, Randomized, Placebo Controlled, Crossover Study to Evaluate the Efficacy of GSK1440115 After a Single Oral Dose in Patients With Asthma

The purpose of this study is to assess bronchodilator effect after single dose administration of GSK1440115 in a population of mild to moderate asthmatic patients.

开始日期2011-08-01

申办/合作机构

Accenture Plc

NCT01202214 / Completed临床1期

A Randomized, Single-Blind, Placebo Controlled, Dose Escalation Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of GSK1440115 After a Single Dose and 7 Days of Repeat Dosing in Healthy Volunteers

The purpose of this study is to describe the safety and tolerability of single and repeat oral doses of GSK1440115 in healthy volunteers.

开始日期2010-09-01

申办/合作机构

Accenture Plc

100 项与 UTS2R 相关的临床结果

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100 项与 UTS2R 相关的转化医学

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0 项与 UTS2R 相关的专利（医药）

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258

项与 UTS2R 相关的文献（医药）

2024-08-22·Journal of Medicinal Chemistry

Expanding Structure–Activity Relationships of Human Urotensin II Peptide Analogues: A Proposed Key Role of the N-Terminal Region for Novel Urotensin II Receptor Modulators

Article

作者: Carotenuto, Alfonso ; Merlino, Francesco ; Grasso, Nicola ; Secondo, Agnese ; Chatenet, David ; d’Emmanuele di Villa Bianca, Roberta ; Bellavita, Rosa ; Sorrentino, Raffaella ; Mitidieri, Emma ; Grieco, Paolo ; Pannaccione, Anna

While the urotensinergic system plays a role in influencing various pathologies, its potential remains untapped because of the absence of therapeutically effective urotensin II receptor (UTR) modulators. Herein, we developed analogues of human urotensin II (hU-II) peptide in which, along with well-known antagonist-oriented modifications, the Glu¹ residue was subjected to single-point mutations. The generated library was tested by a calcium mobilization assay and ex vivo experiments, also in competition with selected ligands. Interestingly, many derivatives showed noncompetitive modulation that was rationalized by the lateral allostery concept applied to a G protein-coupled receptor (GPCR) multimeric model. UPG-108 showed an unprecedented ability to double the efficacy of hU-II, while UPG-109 and UPG-111 turned out to be negative allosteric modulators of UTR. Overall, our investigation will serve to explore and highlight the expanding possibilities of modulating the UTR system through N-terminally modified hU-II analogues and, furthermore, will aim to elucidate the intricate nature of such a GPCR system.

2024-06-01·Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease

Urotensin II receptor deficiency ameliorates ligation-induced carotid intimal hyperplasia partially through the RhoA-YAP1 pathway

Article

作者: Wang, Rong ; Liu, Haole ; Li, Yankui ; Xu, Baohui ; Wang, Weirong ; Bai, Liang ; Alam, Naqash ; Li, Kexin ; Cheng, Daxin ; Zhao, Sihai ; Tian, Kangli ; Guo, Jia ; Li, Meng ; He, Xue ; Wei, Panpan ; Liu, Enqi

Intimal hyperplasia (IH) is a common pathological feature of vascular proliferative diseases, such as atherosclerosis and restenosis after angioplasty. Urotensin II (UII) and its receptor (UTR) are widely expressed in cardiovascular tissues. However, it remains unclear whether the UII/UTR system is involved in IH. Right unilateral common carotid artery ligation was performed and maintained for 21 days to induce IH in UTR knockout (UTR^-/-) and wild-type (WT) mice. Histological analysis revealed that compared with WT mice, UTR-deficient mice exhibited a decreased neointimal area, angiostenosis and intima-media ratio. Immunostaining revealed fewer smooth muscle cells (SMCs), endothelial cells and macrophages in the lesions of UTR^-/- mice than in those of WT mice. Protein interaction analysis suggested that the UTR may affect cell proliferation by regulating YAP and its downstream target genes. In vitro experiments revealed that UII can promote the proliferation and migration of SMCs, and western blotting also revealed that UII increased the protein expression of RhoA, CTGF, Cyclin D1 and PCNA and downregulated p-YAP protein expression, while these effects could be partly reversed by urantide. To evaluate the translational value of UTRs in IH management, WT mice were also treated with two doses of urantide, a UTR antagonist, to confirm the benefit of UTR blockade in IH progression. A high dose of urantide (600 μg/kg/day), rather than a low dose (60 μg/kg/day), successfully improved ligation-induced IH compared with that in mice receiving vehicle. The results of the present study suggested that the UII/UTR system may regulate IH partly through the RhoA-YAP signaling pathway.

2024-04-01·Cellular Signalling

Evidence for heterodimerization and functional interaction of the urotensin II and the angiotensin II type 1 receptors

Article

作者: Chatenet, David ; Nassour, Hassan ; Hébert, Terence E ; Devost, Dominic ; Billard, Etienne ; Pétrin, Darlaine ; Sleno, Rory

Despite the observation of synergistic interactions between the urotensinergic and angiotensinergic systems, the interplay between the urotensin II receptor (hUT) and the angiotensin II type 1 receptor (hAT1R) in regulating cellular signaling remains incompletely understood. Notably, the putative interaction between hUT and hAT1R could engender reciprocal allosteric modulation of their signaling signatures, defining a unique role for these complexes in cardiovascular physiology and pathophysiology. Using a combination of co-immunoprecipitation, bioluminescence resonance energy transfer (BRET) and FlAsH BRET-based conformational biosensors, we first demonstrated the physical interaction between hUT and hAT1R. Next, to analyze how this functional interaction regulated proximal and distal hUT- and hAT1R-associated signaling pathways, we used BRET-based signaling biosensors and western blots to profile pathway-specific signaling in HEK 293 cells expressing hUT, hAT1R or both. We observed that hUT-hAT1R heterodimers triggered distinct signaling outcomes compared to their respective parent receptors alone. Notably, co-transfection of hUT and hAT1R has no impact on hUII-induced G_q activation but significantly reduced the potency and efficacy of Ang II to mediate G_q activation. Interestingly, URP, the second hUT endogenous ligand, produce a distinct signaling signature compared to hUII at hUT-hAT1R. Our results therefore suggest that assembly of hUT with hAT1R might be important for allosteric modulation of outcomes associated with specific hardwired signaling complexes in healthy and disease states. Altogether, our work, which potentially explains the interplay observed in native cells and tissues, validates such complexes as potential targets to promote the design of compounds that can modulate heterodimer function selectively.