Catecholaminergic polymorphic ventricular tachycardia(CPVT)is an inherited,lethal ventricular arrhythmia triggered by catecholamines.Mutations in genes that encode cardiac ryanodine receptor(RyR2)and proteins that regulate RyR2 activity cause enhanced diastolic Ca2+release(leak)through the RyR2 channels,resulting in CPVT.Current therapies for CPVT are limited.We found that Z16b,a meroterpenoid isolated from Ganoderma cochlear,inhibited Ca2+spark frequency(CaSF)in R2474S/+cardiomyocytes in a dose-dependent manner,with an IC50 of 3.2 μM.Z16b also dose-dependently suppressed abnormal post-pacing Ca2+release events.Intraperitoneal injection(i.p.)of epinephrine and caffeine stimulated sustained ventricular tachycardia in all R2474S/+mice,while pretreatment with Z16b(0.5 mg/kg,i.p.)prevented ventricular arrhythmia in 9 of 10 mice,and Z16b administration immediately after the onset of VT abolished sVT in 9 of 12 mice.Of translational significance,Z16b significantly inhibited CaSF and abnormal Ca2+release events in human CPVT iPS-CMs.Mechanistically,Z16b interacts with RyR2,enhancing the"zipping"state of the N-terminal and central domains of RyR2.A molecular docking simulation and point mutation and pulldown assays identified Z16b forms hydrogen bonds with Arg626,His1670,and Gln2126 in RyR2 as a triangle shape that anchors the NTD and CD interaction and thus stabilizes RyR2 in a tight"zipping"conformation.Our findings support that Z16b is a novel RyR2 stabilizer that can prevent CPVT.It may also serve as a lead compound with a new scaffold for the design of safer and more efficient drugs for treating CPVT.

Jiang-fan Wan;Gang Wang;Fu-ying Qin;Dan-ling Huang;Yan Wang;Ai-ling Su;Hai-ping Zhang;Yang Liu;Shao-yin Zeng;Chao-liang Wei;Yong-xian Cheng;Jie Liu

Guangdong Key Laboratory of Genome Stability and Human Disease Prevention,Department of Pathophysiology,School of Medicine,Shenzhen University,Shenzhen 518000,China;College of Physics and Optoelectronic Engineering,Shenzhen University,Shenzhen 518060,China;School of Pharmaceutical Sciences,Shenzhen University Health Science Center,Shenzhen 518000,China;Center for Translation Medicine Research and Development,Shenzhen Institute of Advanced Technology,Chinese Academy of Sciences,Shenzhen 518000,China;Center for High Performance Computing,Joint Engineering Research Center for Health Big Data Intelligent Analysis Technology,Shenzhen Institutes of Advanced Technology,Chinese Academy of Sciences,Shenzhen 518000,China;Guangdong Cardiovascular Institute,Guangdong Provincial People's Hospital,Guangdong Academy of Medical Sciences,Guangzhou 510000,China;Guangdong Provincial key laboratory of South China Structure Heart Disease,Department of Pediatric Cardiology,Guangdong Cardiovascular Institute,Guangdong Provincial People's Hospital,Guangdong Academy of Medical Sciences,Guangzhou 510000,China

中国药理学报（英文版）

[1]Jiang-fan Wan;Gang Wang;Fu-ying Qin;Dan-ling Huang;Yan Wang;Ai-ling Su;Hai-ping Zhang;Yang Liu;Shao-yin Zeng;Chao-liang Wei;Yong-xian Cheng;Jie Liu-.Z16b,a natural compound from Ganoderma cochlear is a novel RyR2 stabilizer preventing catecholaminergic polymorphic ventricular tachycardia)[J].中国药理学报（英文版）,2022(09):2340-2350

Z16b,catecholaminergic,Catecholaminergic,meroterpenoid,Ca2+spark,CaSF,R2474S,+cardiomyocytes,+mice,sVT,zipping,Arg626,His1670,Gln2126

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