The proposed study will examine how the ATP-sensitive potassium channel (KATP) in heart muscle is controlled. The work will investigate the interaction of physiological and pharmacological agents in short-and long- term regulation. The specific planned experiments are intended to elucidate the sub-cellular and molecular mechanisms underlying the modulation of KATP channel activity in mammalian heart cells. Whole-cell and patch-clamped preparations from rate and guinea-pig hearts will be used to investigate the mechanisms by which nucleotides inhibit channel activity and by which specific drugs (cromakalim, pinacidil, RP 49356) open the channel. The hypothesis that very long-term modulation of channel activity in response to environmental stimuli will be examined by experiments using tissue from different parts of the heart, and hearts exposed to different workloads. The planned experiments will address the following specific questions: (1) Does channel phosphorylation modulate ATP-sensitivity and is this an in vivo mechanism of channel regulation? The answers to this question will help understanding of the regulation of channel activity over a time-scale of minutes. (2) What kinetic scheme describes the interaction of ATP and other nucleotides with the channel? This investigation is designed to elucidate the short-term (millisecond) regulation of channel behavior. (3) What is the interaction between the KATP channel and the potassium channel opening drugs and sulfonylureas? This investigation will determine the interactions between potassium channel opening drugs and nucleotides in regulating channel behavior. (4) Is there a preferential source of ATP for channel inhibition? The route by which ATP diffuses to the channel is important to our understanding of how the channel is controlled in the intact cell. (5) Do environmental factors (such as mechanical load, hypertrophy, age) influence the numer, or ATP-sensitivity of KATP channels? The results of the proposed experiments, and answers to the above questions, will provide insight into the regulation of ion transport processes at the molecular level. The work will therefore provide information on the interactions between electrical and chemical features of the heart cell, relevant to normal and pathological function. The work should therefore lay the foundations for more rational therapies for myocardial diseases involving metabolic compromise.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cardiovascular and Renal Study Section (CVB)
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Washington University
Schools of Medicine
Saint Louis
United States
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Bohnen, Michael S; Ma, Lijiang; Zhu, Na et al. (2018) Loss-of-Function ABCC8 Mutations in Pulmonary Arterial Hypertension. Circ Genom Precis Med 11:e002087
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
Kirk, Edwin P; Scurr, Ingrid; van Haaften, Gijs et al. (2017) Clinical utility gene card for: CantĂș syndrome. Eur J Hum Genet 25:
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

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