ATP-sensitive potassium (KATP) channels are a major link between cell metabolism and and electrical activity, and in the heart, these channels underlie actiojn potential change sin response to ischemia. Recent evidence also supports a role in early repolarization syndrome (ERS). We have developed innovative new approaches to determine the moelcuelar details of KATP channel regulation, and to assess channel localization and function in the intact heart. During the previous period of support, we developed novel FRET approaches to assessing protein structure dynamics during gating, and to assess channel domain and subunit organization. We also developed novel transgenic animals that raise new questions regarding the role of Kir6.1 subunits in the heart. These studies now lead to three experimental series, addressing the questions regarding (1) the molecular basis of nucleotide gating in KATP, (2) the association rules between Kir6 subunits and (3) the analysis of an animal model of Kir6.1-dependent ERS. The results of proposed experiments will bring insight to the regulation and role of KATP channels in cardiac arrhythmias and will provide information that will ultimately underlie the development of rational therapies for the treatment of cardiac ischemia and arrhythmias.

Public Health Relevance

We are studying the KATP channel which uniquely links energy levels in the heart to its excitability. Defects in this channel underlie human cardiac arrhythmias and we are attempting to understand and explain why, both by studying the innate properties of the channel itself, and by studying the consequences of defective activity in animals. The results of our studies will provide critical information for developing new therapies to treat such defects in humans.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL045742-21
Application #
8600963
Study Section
Special Emphasis Panel (ZRG1-CVRS-F (02))
Program Officer
Wong, Renee P
Project Start
1991-01-01
Project End
2016-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
21
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
Cooper, Paige E; McClenaghan, Conor; Chen, Xingyu et al. (2017) Conserved functional consequences of disease-associated mutations in the slide helix of Kir6.1 and Kir6.2 subunits of the ATP-sensitive potassium channel. J Biol Chem 292:17387-17398
Nichols, Colin G (2016) Adenosine Triphosphate-Sensitive Potassium Currents in Heart Disease and Cardioprotection. Card Electrophysiol Clin 8:323-35
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
Kharade, Sujay V; Nichols, Colin; Denton, Jerod S (2016) The shifting landscape of KATP channelopathies and the need for 'sharper' therapeutics. Future Med Chem 8:789-802
Levin, Mark D; Zhang, Haixia; Uchida, Keita et al. (2015) Electrophysiologic consequences of KATP gain of function in the heart: Conduction abnormalities in Cantu syndrome. Heart Rhythm 12:2316-24
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; Reutter, Heiko; Woelfle, Joachim et al. (2014) CantĂș syndrome resulting from activating mutation in the KCNJ8 gene. Hum Mutat 35:809-13
Nichols, Colin G; Singh, Gautam K; Grange, Dorothy K (2013) KATP channels and cardiovascular disease: suddenly a syndrome. Circ Res 112:1059-72
Li, Anlong; Knutsen, Russell H; Zhang, Haixia et al. (2013) Hypotension due to Kir6.1 gain-of-function in vascular smooth muscle. J Am Heart Assoc 2:e000365
Wang, Shizhen; Makhina, Elena N; Masia, Ricard et al. (2013) Domain organization of the ATP-sensitive potassium channel complex examined by fluorescence resonance energy transfer. J Biol Chem 288:4378-88

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