Control of KATP channel expression by CaMKII: role in heart failure resistance

Summary

Principal Investigator: DENICE HODGSON-ZINGMAN
Abstract: DESCRIPTION (provided by applicant): Heart failure is an enormous public health problem in the United States. Over the past two decades, there has been considerable progress in the treatment of chronic heart failure yet, even with the best of modern therapy, heart failure is stil associated with a 5-year mortality rate of 50%. Therefore, the search for new approaches to treatment and prevention of heart failure is one of the major challenges in medicine. The ATP-sensitive potassium (KATP) channel, one of the most abundant cardiac membrane protein complexes, has the unique ability to adjust membrane excitability in response to changes in the energetic status of the cell. When activated by increased cellular metabolic demand, KATP channel-dependent potassium efflux shortens cardiac action potential duration (APD). This potassium efflux limits sodium and calcium entry into the cell and thus reduces energy requirements for ion homeostasis and contraction, as well as prolongs the diastolic interval that supports myocardial relaxation and replenishment of ATP. Our recent work uncovered that that the ability of the heart to optimize APD and energy utilization depends on the membrane expression level of KATP channels which affects how quickly and efficiently KATP current can adapt to changes in workload. A complete understanding of mechanisms that control membrane KATP channel expression may reveal new avenues to promote cardiac energy efficiency and resistance to heart failure. Based on our preliminary data, we hypothesize that membrane KATP channel expression is coupled with overall cardiac function by calcium/calmodulin dependent protein kinase II (CaMKII). This densely expressed multifunctional kinase targets numerous proteins involved in excitation contraction coupling and excitability to support enhanced cardiac performance, while its persistent activation under pathophysiological conditions promotes cardiomyocyte death and dysfunction. We propose a previously unrecognized downstream signaling pathway of CaMKII activation through phosphorylation of the Kir6.2 pore-forming KATP channel subunit and consequent endocytosis of KATP channels. Under persistent CaMKII activation, the consequent reduction in KATP channel expression would aggravate depletion of cardiac energy resources thus contributing to myocardial injury, cell death and heart failure. We predict that the known beneficial effects on cardiac stress resistance that occur with CaMKII inhibition will depend significantly on membrane retention of KATP channels. In Aim1 we will define the mechanism for CaMKII-dependent endocytosis of KATP channels by use of tagged recombinant KATP channel subunits, confocal immunofluorescence imaging, and molecular biology and patch clamp techniques in cardiomyocytes and HEK293T cells. In Aim 2 we will study heart failure, induced in genetic mouse models with KATP channel expression deficits and cardioselective CaMKII inhibition, to understand the role of CaMKII-dependent KATP channel expression regulation in the generation of the energetic and functional deficits defining heart failure.
Funding Period: 2012-04-16 - 2017-01-31
more information: NIH RePORT

Top Publications

  1. pmc Exercise-induced expression of cardiac ATP-sensitive potassium channels promotes action potential shortening and energy conservation
    Leonid V Zingman
    Department of Internal Medicine, University of Iowa, Carver College of Medicine, Iowa City, IA 52242, USA
    J Mol Cell Cardiol 51:72-81. 2011
  2. pmc Regulation of cardiac ATP-sensitive potassium channel surface expression by calcium/calmodulin-dependent protein kinase II
    Ana Sierra
    Department of Internal Medicine, University of Iowa, Carver College of Medicine, Iowa City, Iowa 52242, USA
    J Biol Chem 288:1568-81. 2013
  3. pmc Sarcolemmal ATP-sensitive potassium channels modulate skeletal muscle function under low-intensity workloads
    Zhiyong Zhu
    Department of Internal Medicine and 2 Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242
    J Gen Physiol 143:119-34. 2014

Detail Information

Publications3

  1. pmc Exercise-induced expression of cardiac ATP-sensitive potassium channels promotes action potential shortening and energy conservation
    Leonid V Zingman
    Department of Internal Medicine, University of Iowa, Carver College of Medicine, Iowa City, IA 52242, USA
    J Mol Cell Cardiol 51:72-81. 2011
    ....
  2. pmc Regulation of cardiac ATP-sensitive potassium channel surface expression by calcium/calmodulin-dependent protein kinase II
    Ana Sierra
    Department of Internal Medicine, University of Iowa, Carver College of Medicine, Iowa City, Iowa 52242, USA
    J Biol Chem 288:1568-81. 2013
    ..This mechanism couples the surface expression of cardiac K(ATP) channels with calcium signaling and reveals new targets to improve cardiac energy efficiency and stress resistance...
  3. pmc Sarcolemmal ATP-sensitive potassium channels modulate skeletal muscle function under low-intensity workloads
    Zhiyong Zhu
    Department of Internal Medicine and 2 Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242
    J Gen Physiol 143:119-34. 2014
    ..These mechanisms may provide a foundation for novel strategies to combat metabolic derangements when energy conservation or dissipation is required. ..

Research Grants30

  1. Gene Therapy with Cardiotropic Vectors for the Treatment of Heart Failure
    Roger J Hajjar; Fiscal Year: 2013
    ....
  2. OXIDATIVE STRESS IN THE KIDNEY IN HYPERTENSION
    Christopher S Wilcox; Fiscal Year: 2013
    ..These are supported by the Administrative, Animal and Bioanalytical Cores. ..
  3. Mechanisms of Atherogenesis in Insulin Resistance
    IRA A TABAS; Fiscal Year: 2013
    ..End of Abstract) ..
  4. Ca-Calmodulin Activated Phosphorylation Signaling Pathways in the Heart
    COURTNEY BLAKE NICHOLS; Fiscal Year: 2013
    ..This will help to identify novel signaling cascades and thereby identify new therapeutic targets for the treatment of heart failure. ..
  5. Regulation of Cardiac Calcium Channels by an Autoinhibitory Signalling Complex
    William A Catterall; Fiscal Year: 2013
    ..These studies will increase understanding of regulation of the heart by the sympathetic nervous system and give essential new insight into the molecular and functional changes in the Cav1.2 signaling complex in heart failure. ..
  6. CELLULAR BIOLOGY OF CARDIAC SODIUM-CALCIUM EXCHANGE
    KENNETH PHILIPSON; Fiscal Year: 2013
    ..This knowledge is essential so that we can learn how to manipulate NCX and cleft Ca as therapeutic targets in patients with heart failure and ischemic cardiac dysfunction. ..
  7. Mechanisms of Ventricular Tachycardia in Lipotoxic Cardiomyopathy
    JOHN PEARCE MORROW; Fiscal Year: 2013
    ..This project seeks to understand the pathophysiology of lipotoxic cardiomyopathy that leads to arrhythmias and sudden death by using animal models. ..
  8. IONIC CONTROL OF CARDIAC MUSCLE CONTRACTION: EC COUPLING
    Donald M Bers; Fiscal Year: 2013
    ..A wide array of approaches will be used to answer key fundamental questions relevant to normal cardiac physiology and pathophysiology (e.g. of heart failure and arrhythmias). ..
  9. IPF Fibroblast Phenotype
    Craig A Henke; Fiscal Year: 2013
    ..A major objective of this Program Project is to inform decisions of the IPF Clinical Network by providing information that can be translated into novel therapeutic strategies for IPF. ..
  10. CARDIOVASCULAR DYNAMICS AND THEIR CONTROL
    John E Hall; Fiscal Year: 2013
    ..End of Abstract) ..