Yoda1 analogue (Dooku1) which antagonizes Yoda1-evoked activation of Piezo1 and aortic relaxation

被引：160

作者：

Evans, Elizabeth L. ^{[1
]}

Cuthbertson, Kevin ^{[2
]}

Endesh, Naima ^{[1
]}

Rode, Baptiste ^{[1
]}

Blythe, Nicola M. ^{[1
]}

Hyman, Adam J. ^{[1
]}

Hall, Sally J. ^{[1
]}

Gaunt, Hannah J. ^{[1
]}

Ludlow, Melanie J. ^{[1
]}

Foster, Richard ^{[2
]}

Beech, David J. ^{[1
]}

机构：

[1] Univ Leeds, Sch Med, Leeds Inst Cardiovasc & Metab Med, LIGHT Bldg,Clarendon Way, Leeds LS2 9JT, W Yorkshire, England

[2] Univ Leeds, Sch Chem, Leeds LS2 9JT, W Yorkshire, England

来源：

BRITISH JOURNAL OF PHARMACOLOGY | 2018年 / 175卷 / 10期

基金：

英国生物技术与生命科学研究理事会; 英国惠康基金; 英国医学研究理事会;

关键词：

ION-CHANNEL; PHARMACOLOGY; 2017/18; CONCISE GUIDE; MUTATIONS; ARCHITECTURE; PUBLICATION;

D O I：

10.1111/bph.14188

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

BACKGROUND AND PURPOSE The mechanosensitive Piezo1 channel has important roles in vascular physiology and disease. Yoda1 is a small-molecule agonist, but the pharmacology of these channels is otherwise limited. EXPERIMENTAL APPROACH Yoda1 analogues were generated by synthetic chemistry. Intracellular Ca2+ and Tl+ measurements were made in HEK 293 or CHO cell lines overexpressing channel subunits and in HUVECs, which natively express Piezo1. Isometric tension recordings were made from rings of mouse thoracic aorta. KEY RESULTS Modification of the pyrazine ring of Yoda1 yielded an analogue, which lacked agonist activity but reversibly antagonized Yoda1. The analogue is referred to as Dooku1. Dooku1 inhibited 2M Yoda1-induced Ca2+-entry with IC(50)s of 1.3M (HEK 293 cells) and 1.5M (HUVECs) yet failed to inhibit constitutive Piezo1 channel activity. It had no effect on endogenous ATP-evoked Ca2+ elevation or store-operated Ca2+ entry in HEK 293 cells or Ca2+ entry through TRPV4 or TRPC4 channels overexpressed in CHO and HEK 293 cells. Yoda1 caused dose-dependent relaxation of aortic rings, which was mediated by an endothelium- and NO-dependent mechanism and which was antagonized by Dooku1 and analogues of Dooku1. CONCLUSION AND IMPLICATIONS Chemical antagonism of Yoda1-evoked Piezo1 channel activity is possible, and the existence of a specific chemical interaction site is suggested with distinct binding and efficacy domains.

引用

页码：1744 / 1759

页数：16

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