Regulator of G protein signaling 17 represents a novel target for treating cisplatin induced hearing loss.
Regulator of G protein signaling 17 represents a novel target for treating cisplatin induced hearing loss.
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G 蛋白信号调节器 17 是治疗顺铂诱导的听力损失的新靶点。
DOI：
10.1038/s41598-021-87387-5
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发表时间：
2021-04-14
影响因子：
4.6
通讯作者：
Ramkumar V
中科院分区：
文献类型：
--
作者：
Dhukhwa A;Al Aameri RFH;Sheth S;Mukherjea D;Rybak L;Ramkumar V
G蛋白信号传导调节因子（Regulators of G protein signaling，RGS）可加速G蛋白的GT3活性，使G蛋白偶联受体（GPCRs）触发的信号迅速终止。几种GPCR的激活，包括大麻素受体2（CB2R）和腺苷A1受体（A1AR），可以防止噪音和药物诱导的耳毒性。一种这样的药物，顺铂，一种用于治疗各种实体瘤的抗癌剂，在实验动物和接受治疗的高比例癌症患者中产生永久性听力损失。在这项研究中，我们发现顺铂诱导RGS17基因的表达，并增加RGS17蛋白的水平，这有助于听力损失的显着比例。RGS 17的敲除可抑制雄性Wistar大鼠中顺铂诱导的听力损失，而RGS 17单独过表达则会导致体内听力损失。此外，RGS17和CB2R负调控彼此的表达。这些数据表明，RGS17通过将细胞保护性GPCR与其正常G蛋白相互作用解偶联来介导顺铂耳毒性，从而减轻这些受体的内源性配体的耳保护作用。因此，RGS17代表了顺铂耳毒性的新介质和治疗听力损失的潜在治疗靶点。
Regulators of G protein signaling (RGS) accelerate the GTPase activity of G proteins to enable rapid termination of the signals triggered by G protein-coupled receptors (GPCRs). Activation of several GPCRs, including cannabinoid receptor 2 (CB2R) and adenosine A1 receptor (A1AR), protects against noise and drug-induced ototoxicity. One such drug, cisplatin, an anticancer agent used to treat various solid tumors, produces permanent hearing loss in experimental animals and in a high percentage of cancer patients who undergo treatments. In this study we show that cisplatin induces the expression of the RGS17 gene and increases the levels of RGS17 protein which contributes to a significant proportion of the hearing loss. Knockdown of RGS17 suppressed cisplatin-induced hearing loss in male Wistar rats, while overexpression of RGS17 alone produced hearing loss in vivo. Furthermore, RGS17 and CB2R negatively regulate the expression of each other. These data suggest that RGS17 mediates cisplatin ototoxicity by uncoupling cytoprotective GPCRs from their normal G protein interactions, thereby mitigating the otoprotective contributions of endogenous ligands of these receptors. Thus, RGS17 represents a novel mediator of cisplatin ototoxicity and a potential therapeutic target for treating hearing loss.
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影响因子：
5.3
作者：
Ghosh S;Sheth S;Sheehan K;Mukherjea D;Dhukhwa A;Borse V;Rybak LP;Ramkumar V
通讯作者：
Ramkumar V
短暂干扰RNA对STAT1的干扰可通过抑制炎症来减弱顺铂诱导的大鼠耳毒性。
影响因子：
9
作者：
通讯作者：
--
影响因子：
3.4
作者：
CANLON, B;HOMBURGER, V;BOCKAERT, J
通讯作者：
BOCKAERT, J
影响因子：
45.3
作者：
Landier, Wendy;Knight, Kristin;Bhatia, Smita
通讯作者：
Bhatia, Smita
影响因子：
6.5
作者：
Lee, Ho-Joo;Rao, Jagadeesh S.;Bazinet, Richard P.
通讯作者：
Bazinet, Richard P.