Scholarlink

<p>Hypertrophic cardiomyopathy (HCM) is a common inherited cardiac disorder often linked to mutations in various genes, including junctophilin-2 (JPH2), a key non-sarcomeric protein essential for forming junctional membrane complexes between the plasma membrane (PM) and endoplasmic/sarcoplasmic reticulum (ER/SR). Deciphering the molecular mechanisms behind these mutations is crucial for the development of effective therapies. In this study, we investigate the pathological effects of the HCM-associated S165F mutation in JPH2. Through integrated structural and biochemical analyses, we demonstrate that the S165F mutation induces an unintended intramolecular interaction in JPH2, disrupting its normal interaction with CaV1.2. This mutation compromises ER-PM junctions and disrupts Ca<sup>2+</sup> signaling, leading to cellular hypertrophy in COS7 and H9c2 cell models. Furthermore, zebrafish overexpressing JPH2_S165F exhibit cardiac dysfunction, including pericardial edema and reduced heart rate. Notably, treatment with the ryanodine receptor agonist PCB-95 ameliorates these phenotypes, underscoring its potential clinical relevance. These findings offer new insights into the molecular mechanisms of JPH2-related HCM and provide a foundation for exploring novel therapeutic interventions.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

S165F mutation-induced Junctophilin-2 autoinhibition impairs Ca2+ signaling in hypertrophic cardiomyopathy

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年11月25日

查看全文
  • Zhiwei Li,
  • Jingxin Wang,
  • Xiao Fang,
  • Haiyang Liu,
  • Wei Liu,
  • Wenqing Zhang,
  • Jianchao Li

摘要

Hypertrophic cardiomyopathy (HCM) is a common inherited cardiac disorder often linked to mutations in various genes, including junctophilin-2 (JPH2), a key non-sarcomeric protein essential for forming junctional membrane complexes between the plasma membrane (PM) and endoplasmic/sarcoplasmic reticulum (ER/SR). Deciphering the molecular mechanisms behind these mutations is crucial for the development of effective therapies. In this study, we investigate the pathological effects of the HCM-associated S165F mutation in JPH2. Through integrated structural and biochemical analyses, we demonstrate that the S165F mutation induces an unintended intramolecular interaction in JPH2, disrupting its normal interaction with CaV1.2. This mutation compromises ER-PM junctions and disrupts Ca2+ signaling, leading to cellular hypertrophy in COS7 and H9c2 cell models. Furthermore, zebrafish overexpressing JPH2_S165F exhibit cardiac dysfunction, including pericardial edema and reduced heart rate. Notably, treatment with the ryanodine receptor agonist PCB-95 ameliorates these phenotypes, underscoring its potential clinical relevance. These findings offer new insights into the molecular mechanisms of JPH2-related HCM and provide a foundation for exploring novel therapeutic interventions.