Delayed Rectifier K Channel Biogenesis is Unveiled in Models of Long QT Syndrome

长 QT 综合征模型中揭示了延迟整流 K 通道生物发生

• 批准号: 7834209
• 负责人: Brian P Delisle
• 金额: $ 15.02万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7834209
• 关键词: Action Potentials; Affect; Arrhythmia; Biochemical; Biogenesis; Cardiac; Cell surface; Cells; Complex; Data; Degradation Pathway; Disease; Endoplasmic Reticulum; Environment; Ethers; Gene-Modified; Genes; Genetic; Genotype; Goals; Health; Heart; Heart Diseases; Human; Imaging Techniques; Inherited; Intracellular Transport; Link; Long QT Syndrome; Mammalian Cell; Membrane; Missense Mutation; Modeling; Molecular; Molecular Chaperones; Mutation; Palpitations; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phenotype; Potassium Channel; Property; Quality Control; Rare Diseases; Research; Seizures; Syncope; Syndrome; Testing; Therapeutic; Transport Vesicles; Voltage-Gated Potassium Channel; cytotoxic; intracellular protein transport; loss of function; new therapeutic target; novel; prevent; protein folding; protein misfolding; public health relevance; sudden cardiac death; trafficking

DESCRIPTION (provided by applicant): Every year, sudden cardiac death claims up to 25,000 people that do not have structural heart disease. Genetic and acquired causes for these cases of sudden cardiac death are increasingly being sought, and hundreds of mutations have been linked to the pro-arrhythmia disease Long QT (LQT) syndrome. Most congenital LQT syndrome patients have mutations in either the KCNQ1 or KCNH2 (human ether a-go-go- related) genes, which encode the voltage-gated K+ channel 1-subunits Kv7.1 and Kv11.1 that underlie the delayed rectifier K+ current in the heart. Studies suggest that KCNQ1 (LQT1) mutations and KCNH2 (LQT2) mutations typically result in a loss of function. Many LQT1 and most LQT2 mutations cause Kv7.1 and Kv11.1 to be retained in Endoplasmic Reticulum (ER), thereby decreasing the number of functional channels expressed at the cell surface. Thus far, mechanisms that increase the ER export and functional expression have only been identified for trafficking deficient LQT2 mutations, and, unfortunately, most of these mechanisms do not have therapeutic potential. In order to rationally develop therapeutic strategies for treating patients with trafficking deficient LQT1 or LQT2 mutations, we propose to study cellular properties that direct the ER retention for LQT1 and LQT2 mutations, and the ER export and trafficking for wild type (WT) Kv7.1 and Kv11.1. We will test that hypothesis: The ER retention of LQT1 and LQT2 mutations is regulated by different components of cellular quality control, and Kv7.1 and Kv11.1 traffic in distinct vesicular transport pathways. We anticipate that modulating interactions between chaperones, co-chaperones, and Kv7.1 or Kv11.1 will selectively increase the functional expression for different trafficking deficient LQT1 and LQT2 mutations, and that the vesicular transport properties for Kv7.1 and Kv11.1 can be manipulated to increase their functional expression. PUBLIC HEALTH RELEVANCE: Every year sudden cardiac death claims up to 25,000 people that do not have structural heart disease. Genetic and acquired causes for these cases of sudden cardiac death are increasingly being identified, and hundreds of mutations have been linked to the pro-arrhythmia disease Long QT (LQT) syndrome. About one in 7,000 people have LQT1 or LQT2, which is caused by mutations in either the KCNQ1 or KCNH2 genes, respectively. These genes encode the voltage-gated K+ channel 1-subunits Kv7.1 and Kv11.1 that underlie the delayed rectifier K+ current in the heart. Studies suggest that LQT1 and LQT2 mutations typically result in a loss of function. The mechanisms that underlie the loss of function varies, but it is now recognized that many of these mutations decrease the number of functional channels expressed at the cell surface, because they are retained inside the cell in the Endoplasmic Reticulum (ER). Thus far, mechanisms that increase the functional expression for these mutations have only been identified for LQT2 and do not have therapeutic potential. In order to rationally develop therapeutic strategies for treating patients with trafficking deficient LQT1 or LQT2 mutations, we propose to study the cellular quality control and vesicular transport properties for Kv7.1 and Kv11.1. We will test the hypothesis that the ER retention of LQT1 and LQT2 mutations is regulated by different components of cellular quality control, and Kv7.1 and Kv11.1 traffic in distinct vesicular transport pathways. We anticipate that we will identify novel ways to increase the functional expression for trafficking deficient LQT1 and LQT2 mutations.

描述（由申请人提供）：每年，心脏突然死亡声称多达25,000人没有结构性心脏病。对于这些突然心脏死亡病例的遗传和获得的原因正在越来越多地寻求，数百个突变与心律不齐的疾病长QT（LQT）综合征有关。大多数先天性LQT综合征患者在KCNQ1或KCNH2（人乙醚A-GO-GO-相关）基因中都有突变，该基因编码了电压门控的K+通道1-辅助KV7.1和KV11.1，这是延迟的整流k+电流的基础。研究表明，KCNQ1（LQT1）突变和KCNH2（LQT2）突变通常会导致功能丧失。许多LQT1和大多数LQT2突变导致KV7.1和KV11.1保留在内质网（ER）中，从而减少了在细胞表面表达的功能通道的数量。到目前为止，增加了ER出口和功能表达的机制仅用于运输缺陷LQT2突变，不幸的是，这些机制中的大多数没有治疗潜力。为了合理地制定治疗贩运缺乏LQT1或LQT2突变患者的治疗策略，我们建议研究指导LQT1和LQT2突变ER保留的细胞性质，以及ER的ER出口和运输野生型（WT）KV7.1和KV11.1。我们将测试假设：LQT1和LQT2突变的ER保留受细胞质量控制的不同组成部分的调节，而KV7.1和KV11.1在不同的囊泡传输途径中的流量。我们预计，调节伴侣，共伴侣和KV7.1或KV11.1之间的相互作用将有选择地增加不同运输缺陷LQT1和LQT2突变的功能表达，并且可以操纵KV7.1和KV11.1的囊泡转运性能以增加其功能表达。公共卫生相关性：每年突然的心脏死亡声称多达25,000人没有结构性心脏病。这些猝死病例的遗传和获得的原因越来越被发现，数百个突变与心律不齐的长QT（LQT）综合征有关。大约有7,000人患有LQT1或LQT2，这分别是由KCNQ1或KCNH2基因突变引起的。这些基因编码电压门控的K+通道1-亚基KV7.1和KV11.1，该基础是心脏中延迟整流器K+电流的基础。研究表明，LQT1和LQT2突变通常会导致功能丧失。构成功能丧失的机制各不相同，但是现在已经认识到，许多突变减少了在细胞表面表达的功能通道的数量，因为它们保留在内质网中的细胞内（ER）。到目前为止，仅确定了针对LQT2的这些突变功能表达的机制，并且没有治疗潜力。为了合理地制定治疗缺乏LQT1或LQT2突变患者的治疗策略，我们建议研究KV7.1和KV11.1的细胞质量控制和囊泡转运性能。我们将测试以下假设：LQT1和LQT2突变的ER保留受细胞质量控制的不同组成部分的调节，而KV7.1和KV11.1在不同的囊泡传输途径中的流量。我们预计我们将确定新的方法来增加运输缺陷LQT1和LQT2突变的功能表达。