Abstract

hERG ion channels are the target for acquired and inherited long QT syndrome (LQTS), diseases leading to polymorphic ventricular fibrillation and sudden death. Previous work in this lab demonstrated that hERGIa subunits are a major component of channels producing the ventricular repolarizing current lKr, thus explaining the underlying cause of LQTS-2 as a loss or reduction of lKr. Most recently, we have identified another subunit of !Kr channels, hERG1b. Encoded by an alternate transcript of the hERG1 gene, hERG1b is identical to hERG1a except for its amino terminus, which is highly divergent. This proposal explores mechanisms by which the differences in the amino termini specify heteromeric assembly, export from the endoplasmic reticulum and stability within the plasma membrane. In addition, we propose to characterize a mutation found in an unmapped LQTS patient potentially representing the first disease mutation specific to hERG1b. These studies are expected to provide novel insights into mechanisms of potassium channel assembly as well as the molecular mechanisms of cardiac arrhythmias.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL081780-03
Application #
7278596
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Wang, Lan-Hsiang
Project Start
2005-09-15
Project End
2010-08-31
Budget Start
2007-09-01
Budget End
2008-08-31
Support Year
3
Fiscal Year
2007
Total Cost
$342,498
Indirect Cost

  Institution

Name
University of Wisconsin Madison
Department
Physiology
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715

  Publications

Jones, David K; Johnson, Ashley C; Roti Roti, Elon C et al. (2018) Localization and functional consequences of a direct interaction between TRIOBP-1 and hERG proteins in the heart. J Cell Sci 131:
Pointer, Kelli B; Clark, Paul A; Eliceiri, Kevin W et al. (2017) Administration of Non-Torsadogenic human Ether-à-go-go-Related Gene Inhibitors Is Associated with Better Survival for High hERG-Expressing Glioblastoma Patients. Clin Cancer Res 23:73-80
Harley, Carol A; Starek, Greg; Jones, David K et al. (2016) Enhancement of hERG channel activity by scFv antibody fragments targeted to the PAS domain. Proc Natl Acad Sci U S A 113:9916-21
Liu, Fang; Jones, David K; de Lange, Willem J et al. (2016) Cotranslational association of mRNA encoding subunits of heteromeric ion channels. Proc Natl Acad Sci U S A 113:4859-64
Jones, David K; Liu, Fang; Dombrowski, Natasha et al. (2016) Dominant negative consequences of a hERG 1b-specific mutation associated with intrauterine fetal death. Prog Biophys Mol Biol 120:67-76
Morais-Cabral, João H; Robertson, Gail A (2015) The enigmatic cytoplasmic regions of KCNH channels. J Mol Biol 427:67-76
Jones, David K; Liu, Fang; Vaidyanathan, Ravi et al. (2014) hERG 1b is critical for human cardiac repolarization. Proc Natl Acad Sci U S A 111:18073-7
Robertson, Gail A (2013) High-resolution scanning patch clamp: life on the nanosurface. Circ Res 112:1088-90
Trudeau, Matthew C; Leung, Lisa M; Roti, Elon Roti et al. (2011) hERG1a N-terminal eag domain-containing polypeptides regulate homomeric hERG1b and heteromeric hERG1a/hERG1b channels: a possible mechanism for long QT syndrome. J Gen Physiol 138:581-92
Abi-Gerges, N; Holkham, H; Jones, E M C et al. (2011) hERG subunit composition determines differential drug sensitivity. Br J Pharmacol 164:419-32

Showing the most recent 10 out of 18 publications