Digitalis-Induced Signaling by Cardiac Na+/K+-ATPase

Summary

Principal Investigator: Amir Askari
Abstract: This application is the resubmission for the competing continuation of a program project grant that was initiated in 1986. The proposed research is the outgrowth of the program's progress during the current funding period, and consists of three projects and two supporting cores, focused on the central theme of digitalis-induced signaling through the cardiac Na*7K+-ATPase. The participating investigators with expertise in membrane biochemistry, protein chemistry, molecular genetics, cell biology, and integrative cardiovascular physiology/ pharmacology will combine their efforts to conduct the following studies: Project I attempts to determine the molecular and cellular mechanisms by which the digitalis-induced activation of class 1A PI3K/Akt pathway leads to cardiac myocyte hypertrophy, and to assess if this seemingly benign hypertrophy is capable of antagonizing the deleterious effects of pathological hypertrophy and its consequences. Project 11 concentrates on the unraveling of the molecular interactions that constitute the formation of the Na+/K+- ATPase/Src complex, and on the evaluation of this complex as the receptor for the initiation of the multiple digitalis-induced signaling pathways and their functional consequences in the heart. Project III focuses on the established digitalis-induced communication between cardiac sarcolemmal Na+/K+-ATPase and ATPsensitive K+ channels of cardiac mitochondria, and proposes to determine the molecular and subcellular mechanisms of this communication, and the resulting digitalis-induced protection of the heart against ischemia-reperfusion injury. The core units are designed to provide administrative support and efficient management of the experimental animals and other shared resources of the program. These proposed studies are expected to expand knowledge on the newly appreciated physiological roles of cardiac NaVK4- ATPase, and to provide the bases for novel approaches to the prevention and treatment of ischemic heart disease and heart failure.
Funding Period: 1986-07-01 - 2015-03-31
more information: NIH RePORT

Top Publications

  1. ncbi Digitalis-induced cell signaling by the sodium pump: on the relation of Src to Na(+)/K(+)-ATPase
    Marjorie E Gable
    Department of Biochemistry and Cancer Biology, College of Medicine and Life Sciences, University of Toledo, Health Science Campus, Toledo, OH 43614, USA
    Biochem Biophys Res Commun 446:1151-4. 2014
  2. pmc Identification of a potential receptor that couples ion transport to protein kinase activity
    Qiqi Ye
    Department of Physiology, University of Toledo College of Medicine, Toledo, Ohio 43614, USA
    J Biol Chem 286:6225-32. 2011
  3. pmc Modulation of Na(+)-K(+)-ATPase cell surface abundance through structural determinants on the α1-subunit
    Sandrine V Pierre
    Department of Physiology and Pharmacology, University of Toledo College of Medicine, Ohio 43614 2598, USA
    Am J Physiol Cell Physiol 300:C42-8. 2011
  4. pmc Progesterone modulation of transmembrane helix-helix interactions between the alpha-subunit of Na/K-ATPase and phospholipid N-methyltransferase in the oocyte plasma membrane
    Gene A Morrill
    Department of Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, New York 10461, USA
    BMC Struct Biol 10:12. 2010
  5. ncbi Alterations of Na+/K+-ATPase function in caveolin-1 knockout cardiac fibroblasts
    Luis E M Quintas
    Department of Physiology and Pharmacology, College of Medicine, University of Toledo, Toledo, OH 43614 5804, USA
    J Mol Cell Cardiol 49:525-31. 2010
  6. pmc Identification of hydroxyxanthones as Na/K-ATPase ligands
    Zhongbing Zhang
    Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
    Mol Pharmacol 77:961-7. 2010
  7. ncbi Critical role of the isoform-specific region in alpha1-Na,K-ATPase trafficking and protein Kinase C-dependent regulation
    Yoann Sottejeau
    Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, Ohio 43614, USA
    Biochemistry 49:3602-10. 2010
  8. ncbi The sodium pump and cardiotonic steroids-induced signal transduction protein kinases and calcium-signaling microdomain in regulation of transporter trafficking
    Jiang Liu
    Department of Medicine, University of Toledo College of Medicine, Toledo, OH, USA
    Biochim Biophys Acta 1802:1237-45. 2010
  9. ncbi Preconditioning by subinotropic doses of ouabain in the Langendorff perfused rabbit heart
    Eric E Morgan
    Department of Physiology and Pharmacology, College of Medicine, University of Toledo, Toledo, OH 43614 5804, USA
    J Cardiovasc Pharmacol 55:234-9. 2010
  10. pmc Spironolactone attenuates experimental uremic cardiomyopathy by antagonizing marinobufagenin
    Jiang Tian
    Department of Medicine, University of Toledo College of Medicine, Toledo, OH 43614 2598, USA
    Hypertension 54:1313-20. 2009

Research Grants

  1. Pathophysiology of Alveolar Epithelial Lung Injury
    Jacob I Sznajder; Fiscal Year: 2013
  2. RAGE and Mechanisms of Vascular Dysfunction
    Shi Fang Yan; Fiscal Year: 2013

Detail Information

Publications59

  1. ncbi Digitalis-induced cell signaling by the sodium pump: on the relation of Src to Na(+)/K(+)-ATPase
    Marjorie E Gable
    Department of Biochemistry and Cancer Biology, College of Medicine and Life Sciences, University of Toledo, Health Science Campus, Toledo, OH 43614, USA
    Biochem Biophys Res Commun 446:1151-4. 2014
    ..We conclude that there is no solid evidence for direct molecular interaction of Src with Na(+)/K(+)-ATPase under physiological conditions. ..
  2. pmc Identification of a potential receptor that couples ion transport to protein kinase activity
    Qiqi Ye
    Department of Physiology, University of Toledo College of Medicine, Toledo, Ohio 43614, USA
    J Biol Chem 286:6225-32. 2011
    ..Together, the data suggest that the Src-coupled α1 Na/K-ATPase may act as a Na(+)/K(+) receptor, allowing salt to regulate cellular function through Src and Src effectors...
  3. pmc Modulation of Na(+)-K(+)-ATPase cell surface abundance through structural determinants on the α1-subunit
    Sandrine V Pierre
    Department of Physiology and Pharmacology, University of Toledo College of Medicine, Ohio 43614 2598, USA
    Am J Physiol Cell Physiol 300:C42-8. 2011
    ....
  4. pmc Progesterone modulation of transmembrane helix-helix interactions between the alpha-subunit of Na/K-ATPase and phospholipid N-methyltransferase in the oocyte plasma membrane
    Gene A Morrill
    Department of Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, New York 10461, USA
    BMC Struct Biol 10:12. 2010
    ..We have characterized this site, using a low affinity ouabain binding isoform of the alpha1-subunit...
  5. ncbi Alterations of Na+/K+-ATPase function in caveolin-1 knockout cardiac fibroblasts
    Luis E M Quintas
    Department of Physiology and Pharmacology, College of Medicine, University of Toledo, Toledo, OH 43614 5804, USA
    J Mol Cell Cardiol 49:525-31. 2010
    ..While depletion of caveolae increases the pumping function of Na(+)/K(+)-ATPase, it suppresses CTS-induced signal transduction, growth, and collagen production in cardiac fibroblasts...
  6. pmc Identification of hydroxyxanthones as Na/K-ATPase ligands
    Zhongbing Zhang
    Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
    Mol Pharmacol 77:961-7. 2010
    ..Thus, we have identified a group of novel Na/K-ATPase ligands that can inhibit the pumping function without stimulating the signaling function of Na/K-ATPase...
  7. ncbi Critical role of the isoform-specific region in alpha1-Na,K-ATPase trafficking and protein Kinase C-dependent regulation
    Yoann Sottejeau
    Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, Ohio 43614, USA
    Biochemistry 49:3602-10. 2010
    ..These findings suggest that a dileucine motif embedded within the Na,K-ATPase alpha1-ISR plays a critical role in the surface expression of Na,K-ATPase alpha1 polypeptides at steady state and in the response to PKC activation...
  8. ncbi The sodium pump and cardiotonic steroids-induced signal transduction protein kinases and calcium-signaling microdomain in regulation of transporter trafficking
    Jiang Liu
    Department of Medicine, University of Toledo College of Medicine, Toledo, OH, USA
    Biochim Biophys Acta 1802:1237-45. 2010
    ....
  9. ncbi Preconditioning by subinotropic doses of ouabain in the Langendorff perfused rabbit heart
    Eric E Morgan
    Department of Physiology and Pharmacology, College of Medicine, University of Toledo, Toledo, OH 43614 5804, USA
    J Cardiovasc Pharmacol 55:234-9. 2010
    ..These data indicate that ouabain administration activates the Na/K-ATPase signaling cascade and protects against ischemic injury in a species with high cardiac Na/K-ATPase sensitivity...
  10. pmc Spironolactone attenuates experimental uremic cardiomyopathy by antagonizing marinobufagenin
    Jiang Tian
    Department of Medicine, University of Toledo College of Medicine, Toledo, OH 43614 2598, USA
    Hypertension 54:1313-20. 2009
    ..Our data suggest that some of the antifibrotic effects of spironolactone may be attributed to antagonism of marinobufagenin signaling through the sodium-potassium-ATPase...
  11. pmc NaKtide, a Na/K-ATPase-derived peptide Src inhibitor, antagonizes ouabain-activated signal transduction in cultured cells
    Zhichuan Li
    Departments of Physiology and Pharmacology, University of Toledo, Toledo, Ohio 43614, USA
    J Biol Chem 284:21066-76. 2009
    ..Taken together, we suggest that pNaKtide may be used as a novel antagonist of ouabain for probing the physiological and pathological significance of the newly appreciated signaling function of Na/K-ATPase and cardiotonic steroids...
  12. pmc Regulation of intracellular cholesterol distribution by Na/K-ATPase
    Yiliang Chen
    Department of Physiology and Pharmacology, College of Medicine, University of Toledo, Toledo, Ohio 43614 2598, USA
    J Biol Chem 284:14881-90. 2009
    ..Moreover, the data also suggest that the plasma membrane Na/K-ATPase-caveolin-1 interaction may represent an important sensing mechanism by which the cells regulate the sterol regulatory element-binding protein pathway...
  13. ncbi MitoKATP activity in healthy and ischemic hearts
    Alexandre D T Costa
    Instituto Carlos Chagas Fiocruz, Rua Prof Algacyr Munhoz Mader, 3775, Curitiba, PR, 81350 010, Brazil
    J Bioenerg Biomembr 41:123-6. 2009
    ....
  14. pmc Regulation of alpha1 Na/K-ATPase expression by cholesterol
    Yiliang Chen
    Department of Physiology and Pharmacology, College of Medicine, University of Toledo, Toledo, Ohio 43614 2598, USA
    J Biol Chem 286:15517-24. 2011
    ....
  15. pmc Impairment of Na/K-ATPase signaling in renal proximal tubule contributes to Dahl salt-sensitive hypertension
    Jiang Liu
    Department of Medicine, University of Toledo College of Medicine, Toledo, Ohio 43614, USA
    J Biol Chem 286:22806-13. 2011
    ..Our data suggested that impairment of Na/K-ATPase signaling and consequent regulation of Na/K-ATPase and NHE3 in renal proximal tubule may contribute to salt-induced hypertension in the Dahl S rat...
  16. pmc Na/K-ATPase mimetic pNaKtide peptide inhibits the growth of human cancer cells
    Zhichuan Li
    Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, Ohio 43614, USA
    J Biol Chem 286:32394-403. 2011
    ..Thus, the new findings demonstrate the in vivo effectiveness of pNaKtide and suggest that the defect in Na/K-ATPase-mediated signal transduction may be targeted for developing new anticancer therapeutics...
  17. pmc Cell signaling associated with Na(+)/K(+)-ATPase: activation of phosphatidylinositide 3-kinase IA/Akt by ouabain is independent of Src
    Jian Wu
    Department of Biochemistry and Cancer Biology, College of Medicine and Life Sciences, University of Toledo Health Science Campus, Toledo, Ohio 43614, United States
    Biochemistry 52:9059-67. 2013
    ....
  18. pmc CEACAM1 loss links inflammation to insulin resistance in obesity and non-alcoholic steatohepatitis (NASH)
    Sonia M Najjar
    Center for Diabetes and Endocrine Research, University of Toledo, Health Science Campus, 3000 Arlington Avenue, Mail Stop 1009, Toledo, OH, 43614, USA
    Semin Immunopathol 36:55-71. 2014
    ..Moreover, we will identify loss of the carcinoembryonic antigen-related cell adhesion molecule 1 as a unifying mechanism linking the immunological and metabolic abnormalities in NASH. ..
  19. pmc Ceacam1 deletion causes vascular alterations in large vessels
    Sonia M Najjar
    Center for Diabetes and Endocrine Research, College of Medicine and Life Sciences, University of Toledo, Health Science Campus, Toledo, Ohio
    Am J Physiol Endocrinol Metab 305:E519-29. 2013
    ..Cc1-/- mice provide a first in vivo demonstration of distinct CEACAM1-dependent hepatic insulin clearance linking hepatic to macrovascular abnormalities...
  20. pmc Expression of mutant α1 Na/K-ATPase defective in conformational transition attenuates Src-mediated signal transduction
    Qiqi Ye
    Department of Physiology, University of Toledo College of Medicine, Toledo Ohio 43614, USA
    J Biol Chem 288:5803-14. 2013
    ....
  21. pmc Different roles of the cardiac Na+/Ca2+-exchanger in ouabain-induced inotropy, cell signaling, and hypertrophy
    Yan Bai
    Department of Biochemistry and Cancer Biology, College of Medicine and Life Sciences, Univ of Toledo, 3000 Arlington Ave, MS 1010, Toledo, Ohio 43614, USA
    Am J Physiol Heart Circ Physiol 304:H427-35. 2013
    ....
  22. pmc Modulation of cardiac Na+,K+-ATPase cell surface abundance by simulated ischemia-reperfusion and ouabain preconditioning
    Aude Belliard
    Department of Biochemistry, College of Medicine, University of Toledo, 3000 Arlington Ave, Toledo, OH 43614, USA
    Am J Physiol Heart Circ Physiol 304:H94-103. 2013
    ..They further suggest that the protection conferred by increased surface expression of Na(+),K(+)-ATPase may be independent of ion transport...
  23. ncbi Interaction of atrial natriuretic peptide and ouabain in the myocardium
    Maoz Nesher
    Department of Medical Neurobiology, Institute for Medical Research Israel Canada, The Hebrew University Hadassah Medical School, Jerusalem, Israel
    Can J Physiol Pharmacol 90:1386-93. 2012
    ....
  24. pmc Mitochondrial ROMK channel is a molecular component of mitoK(ATP)
    D Brian Foster
    Division of Cardiology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
    Circ Res 111:446-54. 2012
    ..Activation of the mitochondrial ATP-sensitive potassium channel (mitoK(ATP)) has been implicated in the mechanism of cardiac ischemic preconditioning, yet its molecular composition is unknown...
  25. ncbi Caveolin-Na/K-ATPase interactions: role of transmembrane topology in non-genomic steroid signal transduction
    Gene A Morrill
    Department of Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, NY 10461, USA
    Steroids 77:1160-8. 2012
    ..Progesterone binding to the α-subunit may thus facilitate CB motif:CAV-1 interaction, which in turn induces helix-helix interaction and generates both a signaling cascade and formation of polar steroids...
  26. pmc Reduction of Na/K-ATPase potentiates marinobufagenin-induced cardiac dysfunction and myocyte apoptosis
    Changxuan Liu
    Department of Physiology and Pharmacology, University of Toledo, Toledo, Ohio 43614, USA
    J Biol Chem 287:16390-8. 2012
    ..Using cultures of neonatal cardiac myocytes, we demonstrated that inhibition of the mTOR pathway by rapamycin also enabled MBG to activate caspase 9 and induce myocyte apoptosis...
  27. pmc The mitochondrial K(ATP) channel--fact or fiction?
    Keith D Garlid
    Department of Biology, Portland State University, Portland, OR 97201 0751, USA
    J Mol Cell Cardiol 52:578-83. 2012
    ..is the evidence for the presence of a K(ATP) channel in mitochondria? Are the pharmacological agents used to modulate mitoK(ATP) activity sufficiently specific to allow the role of these channels in cardioprotection to be established?..
  28. pmc Comparative properties of caveolar and noncaveolar preparations of kidney Na+/K+-ATPase
    Lijun Liu
    Department of Biochemistry and Cancer Biology, University of Toledo Health Science Campus, Toledo, Ohio 43614, United States
    Biochemistry 50:8664-73. 2011
    ....
  29. pmc Changes in sodium pump expression dictate the effects of ouabain on cell growth
    Jiang Tian
    Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, Ohio 43614, USA
    J Biol Chem 284:14921-9. 2009
    ..Taken together, we conclude that changes in the expression of Na/K-ATPase dictate the growth regulatory effects of ouabain on cells...
  30. pmc Cardioprotective signaling to mitochondria
    Keith D Garlid
    Department of Biology, Portland State University, Portland, OR 97201 0751, USA
    J Mol Cell Cardiol 46:858-66. 2009
    ..We review the experimental findings that bear on these hypotheses and other modes of protection involving mitochondria...
  31. pmc Regulation of caveolin-1 membrane trafficking by the Na/K-ATPase
    Ting Cai
    Department of Physiology and Pharmacology, University of Toledo College of Medicine, Health Science Campus, Toledo, OH 43614, USA
    J Cell Biol 182:1153-69. 2008
    ..Finally, Na/K-ATPase knockdown has no effect on processing or exit of Cav1 from the Golgi. Thus, the Na/K-ATPase regulates Cav1 endocytic trafficking and stabilizes the Cav1 plasma membrane pool...
  32. ncbi Identification of a pool of non-pumping Na/K-ATPase
    Man Liang
    Department of Physiology, Pharmacology, Metabolism, and Cardiovascular Sciences, University of Toledo Health Science Campus, Toledo, Ohio 43614, USA
    J Biol Chem 282:10585-93. 2007
    ..Therefore, our new findings suggest that a substantial amount of surface-expressed Na/K-ATPase, at least in some types of cells, may function as non-canonical ouabain-binding receptors...
  33. ncbi The Na,K-ATPase receptor complex: its organization and membership
    Sandrine V Pierre
    Department of Physiology, Pharmacology, Metabolism and Cardiovascular Sciences, Medical University of Ohio, Toledo, OH 43614, USA
    Cell Biochem Biophys 46:303-16. 2006
    ..This article reviews these new developments and provides a comparison of Na,K-ATPase-mediated signal transduction with other receptors and ion transporters...
  34. pmc Ouabain triggers preconditioning through activation of the Na+,K+-ATPase signaling cascade in rat hearts
    Sandrine V Pierre
    Department of Physiology, Pharmacology, Metabolism and Cardiovascular Sciences, Medical University of Ohio, 3035 Arlington Avenue, Toledo, OH 43614 5804, USA
    Cardiovasc Res 73:488-96. 2007
    ....
  35. ncbi Ouabain protects rat hearts against ischemia-reperfusion injury via pathway involving src kinase, mitoKATP, and ROS
    Philippe Pasdois
    Institut National de la Santé et de la Recherche, Médicale U441, University Victor Segalen Bordeaux 2, University Hospital of Bordeaux, Bordeaux, France
    Am J Physiol Heart Circ Physiol 292:H1470-8. 2007
    ..However, only PP2, 5-HD, and MPG blocked ouabain-induced cardioprotection...
  36. ncbi Involvement of Na+/K+-ATPase in hydrogen peroxide-induced hypertrophy in cardiac myocytes
    Lijun Liu
    Department of Physiology, Pharmacology, Metabolism and Cardiovascular Sciences, Medical University of Ohio, Toledo, OH 43614, USA
    Free Radic Biol Med 41:1548-56. 2006
    ..These results, taken together with our prior observations, suggest that ROS may cross talk with Na+/K+-ATPase, leading to the activation of hypertrophic pathways in cardiac myocytes...
  37. ncbi Mitochondrial PKC epsilon and mitochondrial ATP-sensitive K+ channel copurify and coreconstitute to form a functioning signaling module in proteoliposomes
    Martin Jaburek
    Department of Biology, Portland State University, PO Box 751, Portland, Oregon 97207, USA
    Circ Res 99:878-83. 2006
    ..In addition, the activating effect of PKC agonists was reversed by exogenous protein phosphatase 2A. These results demonstrate persistent, functional association of mitochondrial PKC epsilon and mitoK(ATP)...
  38. ncbi Opening mitoKATP increases superoxide generation from complex I of the electron transport chain
    Anastasia Andrukhiv
    Dept of Biology, Portland State Univ, PO Box 751, Portland, OR 97207, USA
    Am J Physiol Heart Circ Physiol 291:H2067-74. 2006
    ..Myxothiazol stimulated mitoK(ATP)-dependent ROS production, whereas rotenone had no effect. This indicates that the superoxide originates in complex I (NADH:ubiquinone oxidoreductase) of the electron transport chain...
  39. ncbi The mechanism by which the mitochondrial ATP-sensitive K+ channel opening and H2O2 inhibit the mitochondrial permeability transition
    Alexandre D T Costa
    Department of Biology, Portland State University, Portland, Oregon 97201 0751, USA
    J Biol Chem 281:20801-8. 2006
    ..4 (+/-0.1) microm. On the basis of these results, we propose that two different PKCepsilon pools regulate this signaling pathway, one in association with mitoK(ATP) and the other in association with MPT...
  40. ncbi Functional characterization of Src-interacting Na/K-ATPase using RNA interference assay
    Man Liang
    Department of Physiology, Pharmacology, Metabolism, and Cardiovascular Sciences, Medical University of Ohio, Toledo, Ohio 43614, USA
    J Biol Chem 281:19709-19. 2006
    ..Taken together, the new findings suggest that LLC-PK1 cells contain a pool of Src-interacting Na/K-ATPase that not only regulates Src activity but also serves as a receptor for ouabain to activate protein kinases...
  41. ncbi Beta-subunit of cardiac Na+-K+-ATPase dictates the concentration of the functional enzyme in caveolae
    Lijun Liu
    Department of Physiology, Pharmacology, Metabolism, and Cardiovascular Sciences, Medical Univ of Ohio, 3035 Arlington Ave, Toledo, OH 43614 5804, USA
    Am J Physiol Cell Physiol 291:C569-78. 2006
    ..Uneven distributions of alpha(1) and beta(1) in early and late endosomes of myocytes suggested different internalization routes of two subunits as a source of selective localization of active Na(+)-K(+)-ATPase in cardiac caveolae...
  42. ncbi Loss of acidification of anterior prostate fluids in Atp12a-null mutant mice indicates that nongastric H-K-ATPase functions as proton pump in vivo
    Nikolay B Pestov
    Dept of Physiology, Pharmacology, Metabolism, and Cardiovascular Sciences, Med Univ of Ohio, 3035 Arlington Ave, Toledo, OH 43614, USA
    Am J Physiol Cell Physiol 291:C366-74. 2006
    ....
  43. ncbi Inhibition of cardiac contractility by 5-hydroxydecanoate and tetraphenylphosphonium ion: a possible role of mitoKATP in response to inotropic stress
    Keith D Garlid
    Portland State University, Portland, Oregon, USA
    Am J Physiol Heart Circ Physiol 291:H152-60. 2006
    ..These results indicate a physiological role for mitoKATP in inotropy and, by extension, in heart failure...
  44. pmc Characterization of hampin/MSL1 as a node in the nuclear interactome
    Ruslan I Dmitriev
    Shemyakin Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, Russia
    Biochem Biophys Res Commun 355:1051-7. 2007
    ..Reconstruction of a fragment of mammalian interactome suggests that hampin may be linked to diverse regulatory processes in the nucleus...
  45. pmc Role of homologous ASP334 and GLU319 in human non-gastric H,K- and Na,K-ATPases in cardiac glycoside binding
    Rossen Radkov
    Department of Physiology, Pharmacology, Metabolism, and Cardiovascular Sciences, University of Toledo College of Medicine, Toledo, OH 43614, USA
    Biochem Biophys Res Commun 356:142-6. 2007
    ..These results provide a strong support for the orientation of ouabain in its biding site with its sugar moiety interacting directly with the second extracellular loop...
  46. ncbi On the importance and mechanism of amplification of digitalis signal through Na+/K+-ATPase
    Lijun Liu
    Department of Physiology, Pharmacology, Metabolism, and Cardiovascular Sciences Medical University of Ohio, Toledo, Ohio 43614 5804, USA
    Cell Mol Biol (Noisy-le-grand) 52:28-30. 2006
    ..The upstream location of both mechanisms suggests that similar amplifications also occur in other cell types with different digitalis downstream effects; e.g., stimulation of proliferation or hypertrophy...
  47. ncbi The Na-K-ATPase and calcium-signaling microdomains
    Jiang Tian
    Department of Physiology and Pharmacology, University of Toledo Health Science Campus, Toledo, Ohio, USA
    Physiology (Bethesda) 23:205-11. 2008
    ..This review focuses on the unique properties of the Na-K-ATPase and its role in the formation of different calcium-signaling microdomains...
  48. pmc Conditioning the heart induces formation of signalosomes that interact with mitochondria to open mitoKATP channels
    Casey L Quinlan
    Department of Biology, Portland State University, PO Box 751, Portland, OR 97201 0751, USA
    Am J Physiol Heart Circ Physiol 295:H953-H961. 2008
    ..These results provide initial support for a novel mechanism for signal transmission from a plasma membrane receptor to mitoKATP channels...
  49. ncbi Differential increase of mitochondrial matrix volume by sevoflurane in isolated cardiac mitochondria
    Matthias L Riess
    Department of Anesthesiology, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226, USA
    Anesth Analg 106:1049-55, table of contents. 2008
    ..We investigated whether sevoflurane increases MMV and if this increase is mediated by mK(ATP) channel opening...
  50. ncbi The Na/K-ATPase/Src complex and cardiotonic steroid-activated protein kinase cascades
    Zhichuan Li
    Department of Physiology and Pharmacology, University of Toledo College of Medicine, Health Science Campus, Mail Stop 1008, 3000 Arlington Avenue, Toledo, OH 43614 2598, USA
    Pflugers Arch 457:635-44. 2009
    ....
  51. ncbi Isoform specificity of Na-K-ATPase-mediated ouabain signaling
    Sandrine V Pierre
    Dept of Physiology and Pharmacology, Univ of Toledo College of Medicine, 3035 Arlington Ave, Toledo, OH 43614 5804, USA
    Am J Physiol Renal Physiol 294:F859-66. 2008
    ....
  52. ncbi cGMP signalling in pre- and post-conditioning: the role of mitochondria
    Alexandre D T Costa
    Department of Biology, Portland State University, PO Box 751, Portland, OR 97201, USA
    Cardiovasc Res 77:344-52. 2008
    ..The resulting ROS then activate a second PKC pool which, through another signal transduction pathway termed the mediator pathway, causes inhibition of MPT and reduction in cell death...
  53. ncbi Regulation of inositol 1,4,5-trisphosphate receptor-mediated calcium release by the Na/K-ATPase in cultured renal epithelial cells
    Ying Chen
    Department of Physiology and Pharmacology, University of Toledo, College of Medicine, Toledo, Ohio 43614, USA
    J Biol Chem 283:1128-36. 2008
    ..Finally, we observed that the alpha1 knockdown was also effective in attenuating ER Ca(2+) release provoked by angiotensin II and epidermal growth factor...
  54. ncbi Identification of a PKCepsilon-dependent regulation of myocardial contraction by epicatechin-3-gallate
    Daxiang Li
    Department of Physiology and Pharmacology, Health Science Campus, University of Toledo, 3000 Arlington Avenue, Toledo, OH 43614 2598, USA
    Am J Physiol Heart Circ Physiol 294:H345-53. 2008
    ..Together, these findings indicate that ECG can regulate myocardial contractility via a novel PKCepsilon-dependent signaling pathway...
  55. pmc Progesterone binding to the alpha1-subunit of the Na/K-ATPase on the cell surface: insights from computational modeling
    Gene A Morrill
    Department of Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, NY 10461, USA
    Steroids 73:27-40. 2008
    ..Peptide flexibility undergoes a maximal transition near the midway point in the M1-M2 loop, suggesting that folding occurs within the loop, which further stabilizes progesterone binding...
  56. ncbi Association of PI3K-Akt signaling pathway with digitalis-induced hypertrophy of cardiac myocytes
    Lijun Liu
    Department of Physiology, Pharmacology, Metabolism, and Cardiovascular Sciences, The University of Toledo College of Medicine, Toledo, Ohio 43614 2598, USA
    Am J Physiol Cell Physiol 293:C1489-97. 2007
    ....
  57. ncbi Interactions of K+ATP channel blockers with Na+/K+-ATPase
    Lijun Liu
    Department of Physiology, Pharmacology, Metabolism, and Cardiovascular Sciences, The University of Toledo College of Medicine, Mail Stop 1008, Health Science Campus, 3000 Arlington Avenue, Toledo, OH 43614 2598, USA
    Mol Cell Biochem 306:231-7. 2007
    ....
  58. pmc Evolution of Na,K-ATPase beta m-subunit into a coregulator of transcription in placental mammals
    Nikolay B Pestov
    Department of Physiology and Pharmacology, University of Toledo College of Medicine, 3000 Arlington Avenue, Toledo, OH 43614, USA
    Proc Natl Acad Sci U S A 104:11215-20. 2007
    ..Thus, orthologous vertebrate ATP1B4 genes represent an instance of gene cooption that created fundamental changes in the functional properties of the encoded proteins...
  59. pmc Binding of Src to Na+/K+-ATPase forms a functional signaling complex
    Jiang Tian
    Department of Pharmacology, Medical University of Ohio, Toledo, OH 43614, USA
    Mol Biol Cell 17:317-26. 2006
    ..These new findings illustrate a novel molecular mechanism of signal transduction involving the interaction of a P-type ATPase and a nonreceptor tyrosine kinase...

Research Grants30

  1. Pathophysiology of Alveolar Epithelial Lung Injury
    Jacob I Sznajder; Fiscal Year: 2013
    ..The insights gained from the data generated from these studies will provide novel molecular targets for the development of new therapeutic strategies to treat patients with lung injury. ..
  2. RAGE and Mechanisms of Vascular Dysfunction
    Shi Fang Yan; Fiscal Year: 2013
    ..Using novel and state-of-the-art techniques, floxed mice and molecular approaches to gene regulation, we are well-positioned to lead the study of RAGE in the next cycle of this Program. ..