ATP-sensitive potassium (KATP) channels are a major link between cell metabolism and electrical activity, and in the heart, these channels underlie actiojn potential changes in 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 #
2R01HL045742-19
Application #
8238583
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
2012-01-01
Budget End
2012-12-31
Support Year
19
Fiscal Year
2012
Total Cost
$380,000
Indirect Cost
$130,000
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; 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
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
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
Goettsch, Claudia; Hutcheson, Joshua D; Aikawa, Elena (2013) MicroRNA in cardiovascular calcification: focus on targets and extracellular vesicle delivery mechanisms. Circ Res 112:1073-84
Wang, Shizhen; Lee, Sun-Joo; Heyman, Sarah et al. (2012) Structural rearrangements underlying ligand-gating in Kir channels. Nat Commun 3:617
Sellitto, Angela D; Al-Dadah, Ashraf S; Schuessler, Richard B et al. (2011) An open sarcolemmal adenosine triphosphate-sensitive potassium channel is necessary for detrimental myocyte swelling secondary to stress. Circulation 124:S70-4
Zhang, Hai Xia; Akrouh, Alejandro; Kurata, Harley T et al. (2011) HMR 1098 is not an SUR isotype specific inhibitor of heterologous or sarcolemmal K ATP channels. J Mol Cell Cardiol 50:552-60
Flagg, Thomas P; Enkvetchakul, Decha; Koster, Joseph C et al. (2010) Muscle KATP channels: recent insights to energy sensing and myoprotection. Physiol Rev 90:799-829
Zhang, Haixia; Flagg, Thomas P; Nichols, Colin G (2010) Cardiac sarcolemmal K(ATP) channels: Latest twists in a questing tale! J Mol Cell Cardiol 48:71-5

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