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

Grants and Contracts Details


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 (LOT) syndrome. Most congenital LQT syndrome patients have mutations in either the KCNQI or KCNH2 (human ether a-go-go- related) genes, which encode the voltage-gated K~ channel a-subunits Kv7. 1 and Kvl 1.1 that underlie the delayed rectifier K~ current in the heart. Studies suggest that KCNQI (LQT1) mutations and KCNH2 (LQT2) mutations typically result in a loss of function. Many LQT1 and most LQT2 mutations cause Kv7.1 and Kvl 1.1 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 LQTI 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 Kvl 1.1. We will test that hypothesis: The ER retention of LQTI and LQT2 mutations is regulated by different components of cellular quality control, and Kv7. I and KY! 1.1 traffic in distinct vesicular transport pathways. We anticipate that modulating interactions between chaperones, co-chaperones, and Kv7.1 or Kvl 1.1 will selectively increase the functional expression for different trafficking deficient LQT1 and LQT2 mutations, and that the vesicular transport properties for Kv7.1 and Kvl 1.1 can be manipulated to increase their functional expression.
Effective start/end date4/15/083/31/15


  • National Heart Lung and Blood Institute: $1,462,070.00


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