Sulfonylurea receptors (SURs) provide a unique link between cardiac metabolism and excitability. Previous efforts on this project have demonstrated that both SUR1 and SUR2 genes are expressed in the heart, with spatial and pathological variability in different regions. Because these subunits confer different metabolic and pharmacologic sensitivities to KATP channels, this realization means that cardiac KATP channel activation may vary regionally and with disease state. Additional studies suggest that differentially spliced versions of the proteins may be expressed in the heart and confer differential functional consequences. The development of novel cell biological tools and transgenic animals have allowed us to generate extensive preliminary data that lead us to propose experiments using biochemical, cell biological and physiological approaches to reach a full understanding of the nature and role of SUR subunit variation in the heart. They are motivated by our discovery of differential subunit expression and consequent functional differences within the mouse heart based on analysis of genetically modified animals, and encompass both mechanistic studies of expression control, and studies of the functional consequences in model systems and human hearts.

Public Health Relevance

Sudden cardiac death due to arrhythmias annually accounts for >300,000 deaths in the U.S.A. and is closely associated with 'metabolic syndrome'. We are focused on SUR proteins which provide a unique link between cardiac metabolism and excitability, to understand how they are regulated within the heart and how they control heart function, in order to help develop new therapies to treat sudden cardiac death and arrhythmias.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL095010-06
Application #
8606232
Study Section
Special Emphasis Panel (ZRG1-CVRS-N (02))
Program Officer
Krull, Holly
Project Start
2008-12-15
Project End
2018-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
6
Fiscal Year
2014
Total Cost
$342,000
Indirect Cost
$117,000
Name
Washington University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Levin, Mark D; Singh, Gautam K; Zhang, Hai Xia et al. (2016) K(ATP) channel gain-of-function leads to increased myocardial L-type Ca(2+) current and contractility in Cantu syndrome. Proc Natl Acad Sci U S A 113:6773-8
Nichols, Colin G (2016) Adenosine Triphosphate-Sensitive Potassium Currents in Heart Disease and Cardioprotection. Card Electrophysiol Clin 8:323-35
Nelson, Peter T; Jicha, Gregory A; Wang, Wang-Xia et al. (2015) ABCC9/SUR2 in the brain: Implications for hippocampal sclerosis of aging and a potential therapeutic target. Ageing Res Rev 24:111-25
Cooper, Paige E; Sala-Rabanal, Monica; Lee, Sun Joo et al. (2015) Differential mechanisms of Cantú syndrome-associated gain of function mutations in the ABCC9 (SUR2) subunit of the KATP channel. J Gen Physiol 146:527-40
Varga, Zoltan; Zhu, Wandi; Schubert, Angela R et al. (2015) Direct Measurement of Cardiac Na+ Channel Conformations Reveals Molecular Pathologies of Inherited Mutations. Circ Arrhythm Electrophysiol 8:1228-39
Arakel, Eric C; Brandenburg, Sören; Uchida, Keita et al. (2014) Tuning the electrical properties of the heart by differential trafficking of KATP ion channel complexes. J Cell Sci 127:2106-19
Raphemot, Rene; Swale, Daniel R; Dadi, Prasanna K et al. (2014) Direct activation of β-cell KATP channels with a novel xanthine derivative. Mol Pharmacol 85:858-65
Sulkin, Matthew S; Widder, Emily; Shao, Connie et al. (2013) Three-dimensional printing physiology laboratory technology. Am J Physiol Heart Circ Physiol 305:H1569-73
Nichols, Colin G; Singh, Gautam K; Grange, Dorothy K (2013) KATP channels and cardiovascular disease: suddenly a syndrome. Circ Res 112:1059-72
Zhang, Hai Xia; Silva, Jonathan R; Lin, Yu-Wen et al. (2013) Heterogeneity and function of K(ATP) channels in canine hearts. Heart Rhythm 10:1576-83

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