Yoda1 analogue (Dooku1) which antagonizes Yoda1-evoked activation of Piezo1 and aortic relaxation.
Yoda1 analogue (Dooku1) which antagonizes Yoda1-evoked activation of Piezo1 and aortic relaxation.
复制标题
DOI：
10.1111/bph.14188
复制
发表时间：
2018-05
影响因子：
7.3
通讯作者：
Beech DJ
中科院分区：
文献类型：
--
作者：
Evans EL;Cuthbertson K;Endesh N;Rode B;Blythe NM;Hyman AJ;Hall SJ;Gaunt HJ;Ludlow MJ;Foster R;Beech DJ
机械敏感的Piezo1通道在血管生理学和疾病中具有重要作用。Yoda1是一种小分子激动剂，但这些通道的药理作用在其他方面是有限的。Yoda1类似物是由合成化学产生的。在HEK 293或CHO细胞系过度表达通道亚基以及在天然表达Piezo1的HUVECs中进行了细胞内钙和TL+的测量。用小鼠胸主动脉环作等长张力记录。对Yoda1的吡嗪环进行修饰，得到一种类似物，该类似物缺乏激动剂活性，但可逆地拮抗Yoda1。这个类比被称为杜库1。杜库1可抑制2μM Yoda1诱导的钙内流，其IC50分别为1.3hμM(HEK293细胞)和1.5hμM(HUVEC)，但不能抑制构成Piezo1通道的活动。对内源性ATP诱导的细胞内钙升高、HEK 293细胞内钙通道操作的钙内流以及CHO和HEK 293细胞中高表达的TRPV4或TRPC4通道内钙内流无明显影响。Yoda1引起剂量依赖性的主动脉环松弛，这是由内皮和NO依赖的机制介导的，并被Dooku1及其类似物拮抗。Yoda1诱发的Piezo1通道活性可能存在化学拮抗作用，并且存在具有不同结合域和效应域的特定化学相互作用部位。
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. 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. 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 2 μM Yoda1‐induced Ca2+‐entry with IC50s of 1.3 μM (HEK 293 cells) and 1.5 μM (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. 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.
登录
查看更多内容
DOI：
10.1002/anie.201411511
发表时间：
2015-03-16
期刊：
Angewandte Chemie (International ed. in English)
影响因子：
--
作者：
Akbulut Y;Gaunt HJ;Muraki K;Ludlow MJ;Amer MS;Bruns A;Vasudev NS;Radtke L;Willot M;Hahn S;Seitz T;Ziegler S;Christmann M;Beech DJ;Waldmann H
通讯作者：
Waldmann H
影响因子：
25
作者：
Koser DE;Thompson AJ;Foster SK;Dwivedy A;Pillai EK;Sheridan GK;Svoboda H;Viana M;Costa LD;Guck J;Holt CE;Franze K
通讯作者：
Franze K
影响因子：
16.6
作者：
Coste, Bertrand;Murthy, Swetha E.;Mathur, Jayanti;Schmidt, Manuela;Mechioukhi, Yasmine;Delmas, Patrick;Patapoutian, Ardem
通讯作者：
Patapoutian, Ardem
影响因子：
2.6
作者：
Outzen EM;Zaki M;Abdolalizadeh B;Sams A;Boonen HC;Sheykhzade M
通讯作者：
Sheykhzade M
影响因子：
7.7
作者：
Guo YR;MacKinnon R
通讯作者：
MacKinnon R