Sigma non-opioid receptor 1 is a potential therapeutic target for long QT syndrome.
Sigma non-opioid receptor 1 is a potential therapeutic target for long QT syndrome.
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Sigma非阿片受体1是长QT综合征的潜在治疗靶标。
DOI：
10.1038/s44161-021-00016-2
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发表时间：
2022-03
期刊：
影响因子：
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通讯作者：
Yazawa, Masayuki
中科院分区：
文献类型：
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作者：
Song, LouJin;Bekdash, Ramsey;Morikawa, Kumi;Quejada, Jose R;Klein, Alison D;Aina-Badejo, Danielle;Yoshida, Kazushige;Yamamoto, Hannah E;Chalan, Amy;Yang, Risako;Patel, Achchhe;Sirabella, Dario;Lee, Teresa M;Joseph, Leroy C;Kawano, Fuun;Warren, Junco S;Soni, Rajesh K;Morrow, John P;Yazawa, Masayuki
编码钙通道CaV1.2的CACNA1C基因的一些错义功能获得突变可导致危及生命的长QT综合征，称为Timothy综合征，目前尚无临床有效的治疗方法。在这里，我们报告了sigma非阿片类细胞内受体1 （SIGMAR1）的药物靶向可以恢复由钾通道错导转运突变引起的Timothy综合征和两种常见的长QT综合征1型（LQTS1）和2型（LQTS2）患者产生的ipsc衍生心肌细胞的电生理功能。电生理记录显示，fda批准的止咳药右美沙芬可以作为SIGMAR1的激动剂，缩短Timothy综合征心肌细胞和LQTS1和LQTS2人细胞模型的延长动作电位。在体内实验中，右美沙芬还能使Timothy综合征模型小鼠延长的QT间期正常化。总的来说，我们的研究表明SIGMAR1是Timothy综合征以及其他遗传性心律失常（如LQTS1和LQTS2）的潜在治疗靶点。
Some missense gain-of-function mutations in CACNA1C gene, encoding calcium channel CaV1.2, cause a life-threatening form of long QT syndrome named Timothy syndrome, with currently no clinically-effective therapeutics. Here we report that pharmacological targeting of sigma non-opioid intracellular receptor 1 (SIGMAR1) can restore electrophysiological function in iPSC-derived cardiomyocytes generated from patients with Timothy syndrome and two common forms of long QT syndrome, type 1 (LQTS1) and 2 (LQTS2), caused by missense trafficking mutations in potassium channels. Electrophysiological recordings demonstrate that an FDA-approved cough suppressant, dextromethorphan, can be used as an agonist of SIGMAR1, to shorten the prolonged action potential in Timothy syndrome cardiomyocytes and human cellular models of LQTS1 and LQTS2. When tested in vivo, dextromethorphan also normalized the prolonged QT intervals in Timothy syndrome model mice. Overall, our study demonstrates that SIGMAR1 is a potential therapeutic target for Timothy syndrome and possibly other inherited arrhythmias such as LQTS1 and LQTS2.