ATP-sensitive K+ (KATP) channels are present at high density throughout the myocardium. This project seeks to understand the cellular and molecular basis for differential KATP channel properties in the atrium and ventricle, and to understand the consequences of this differential make-up for the pharmacological and pathophysiological role of these channels. Preliminary studies show that sulfonylurea receptor (SUR) isoforms are critical determinants of tissue-specific KATP make-up and function. These studies also highlight differential regulation of KATP channels by SUR1 and SUR2A with SUR1 generating more active channels under physiological conditions. Extensive preliminary data indicate that, while SUR2A is likely the primary SUR subunit in the ventricle, SUR1 is a requisite subunit in the atrium, thereby giving rise to the differential pharmacological activation profiles in the two tissues. Preliminary studies also show that, while Kir6.2 knockout has detrimental consequences for the response to ischemia, knockout of SUR1 is beneficial. In order to extend these preliminary findings and explore their implications, three specific aims are proposed, addressing the following questions: (1) What are the subunits that make up the KATP channel in different regions of the heart;(2) What are the pathophysiological and pharmacological properties of the atrial KATP conductance;(3) What is the role of atrial KATP in cardiac pathophysiology and arrhythmia generation? In order to achieve these aims, a series of novel tools have been developed, including a novel specific anti-SUR1 antibody, and appropriate model systems developed through various collaborations. The project will use a multi-level approach to the problem-from molecular analysis of transcripts and proteins to cellular, tissue and whole animal studies. The results of the proposed experiments will define the regional make-up of the cardiac KATP channel and the role of these channels in the generation of arrhythmias and the cardiac response to ischemia.

Public Health Relevance

Relevance Myocardial ischemia, lack of blood flow resulting from blockade of coronary blood vessels, is a major cause of cardiac disease and death. Understanding the cardiac response to ischemia is thus critical for development of appropriate therapies. In addition, cardiac arrhythmias, particularly atrial fibrillation, are major causes of morbidity and mortality. ATP-sensitive potassium channels (KATP) in the heart cell membranes are regulated in a complex way by the cellular metabolic state. Because of this, these channels are major sensors of ischemia, linking metabolic state to electrical activity and hence to cardiac function. They are present at very high density and when activated can lead to re-entrant arrhythmias, including atrial arrhythmia. Achievement of the goal of this project-understanding of the make-up of KATP channels in different regions of the heart, and the functional consequences of this differential make-up-will thus provide essential information that will lead to the development of rational therapies for the treatment of cardiac ischemia and arrhythmias.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL095010-04
Application #
8197281
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Krull, Holly
Project Start
2008-12-15
Project End
2013-01-31
Budget Start
2011-12-01
Budget End
2013-01-31
Support Year
4
Fiscal Year
2012
Total Cost
$376,200
Indirect Cost
$128,700
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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