The ATP-sensitive potassium channel (KATP) plays important physiological and pathophysiological roles in heart, pancreas, brain, vascular smooth muscle. Particularly in heart, KATP participates in ischemic arrhythmias and myocardial preservation. Regulation of KATP is complex. This proposal focuses on two aspects of KATP regulation: effects of cytoplasmic acidosis and effects of anionic phospholipids, both of which may be important in ischemia. This focus is motivated by previous work of the Principal Investigators on native cardiac KATP, by the recent availability of KATP clones (co- expressed BIR/SUR1 and KATP/SUR2), and by a structural hypothesis of phospholipid effects involving the cytoplasmic C-tail of the KATP. In the first aim, detailed characterization of clones KATPs will be performed and compared with native KATP. In the second aim, the effects of acidosis, in combination with other conditions found in ischemia, will be investigated in native KATP from acutely isolated cardiac cells. In the third aim, the effects of anionic phospholipids on native and cloned KATP and other related inward rectifier channel function will be investigated. In the fourth aim, regulation of KATP by native phospholipids and their regulatory enzymes (phosphatases and kinases) will be investigated using a novel phospholipid kinase. In the fifth aim, the 'C-terminus tethering' hypothesis for phospholipid effects will be tested using recombinant DNA technology including site directed mutagenesis, deletions, and chimera. Although the motivation for the studies is to account at the molecular level for effects of ischemic conditions on KATP, the expected results are likely to have wide implications for the structure/function of the superfamily of inward rectifier potassium channels, and will also have implications for the physiology of many tissues in addition to heart.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL057414-04
Application #
6183803
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Project Start
1997-09-01
Project End
2002-08-31
Budget Start
2000-09-01
Budget End
2001-08-31
Support Year
4
Fiscal Year
2000
Total Cost
$267,065
Indirect Cost
Name
University of Wisconsin Madison
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Yang, Kai-Chien; Kyle, John W; Makielski, Jonathan C et al. (2015) Mechanisms of sudden cardiac death: oxidants and metabolism. Circ Res 116:1937-55
Fahrenbach, John P; Stoller, Douglas; Kim, Gene et al. (2014) Abcc9 is required for the transition to oxidative metabolism in the newborn heart. FASEB J 28:2804-15
Aggarwal, Nitin T; Shi, Nian-Qing; Makielski, Jonathan C (2013) ATP-sensitive potassium currents from channels formed by Kir6 and a modified cardiac mitochondrial SUR2 variant. Channels (Austin) 7:493-502
Aggarwal, Nitin T; Makielski, Jonathan C (2013) Redox control of cardiac excitability. Antioxid Redox Signal 18:432-68
Stoller, Douglas A; Fahrenbach, John P; Chalupsky, Karel et al. (2010) Cardiomyocyte sulfonylurea receptor 2-KATP channel mediates cardioprotection and ST segment elevation. Am J Physiol Heart Circ Physiol 299:H1100-8
Aggarwal, Nitin T; Pravdic, Danijel; McNally, Elizabeth M et al. (2010) The mitochondrial bioenergetic phenotype for protection from cardiac ischemia in SUR2 mutant mice. Am J Physiol Heart Circ Physiol 299:H1884-90
Ye, Bin; Kroboth, Stacie L; Pu, Jie-Lin et al. (2009) Molecular identification and functional characterization of a mitochondrial sulfonylurea receptor 2 splice variant generated by intraexonic splicing. Circ Res 105:1083-93
Pu, Jie-Lin; Ye, Bin; Kroboth, Stacie L et al. (2008) Cardiac sulfonylurea receptor short form-based channels confer a glibenclamide-insensitive KATP activity. J Mol Cell Cardiol 44:188-200
Eckhardt, Lee L; Farley, Amanda L; Rodriguez, Esther et al. (2007) KCNJ2 mutations in arrhythmia patients referred for LQT testing: a mutation T305A with novel effect on rectification properties. Heart Rhythm 4:323-9
Kakkar, Rahul; Ye, Bin; Stoller, Douglas A et al. (2006) Spontaneous coronary vasospasm in KATP mutant mice arises from a smooth muscle-extrinsic process. Circ Res 98:682-9

Showing the most recent 10 out of 16 publications