Digitalis drugs (cardiac glycosides, cardiotonic steroids) have been valuable for the management of heart failure and cardiac arrhythmias. Recent studies have demonstrated that the Na/K-ATPase has a novel receptor function in addition to its well described pumping function;i.e., in response to a ligand-like effect of a digitalis compound, Na/K-ATPase activates protein tyrosine kinases. Specifically, we have shown that Na/K-ATPase directly interacts with Src to form a functional digitalis receptor, and ouabain binding to this receptor stimulates the associated Src kinase. This, in turn, results in the increased protein tyrosine phosphorylation and recruitment of protein kinases and lipid kinases to form a functional signalosome that transmits the ouabain signal to different intracellular compartments. Concomitantly, activation of this receptor also induces endocytosis of the signalosome which may terminate the signaling events, or exert various intracellular effects. Moreover, we have recently mapped the interaction domains between the or subunit of Na/K-ATPase and Src. These interactions illustrate a unique and Na/K-ATPase-specific cellular mechanism of Src regulation. Furthermore, we have been able to target the identified interacting domains, and have developed a cci-specific peptide that disrupts the formation of Na/K-ATPase/Src receptor complex and inhibits Src activity. This application is built upon these new discoveries and preliminary findings, and is aimed to further delineate the molecular interactions that constitute the formation of the Na/K-ATPase/Src receptor complex, and to evaluate the functionality of this receptor in digitalis-activated signal transduction. To accomplish these goals, we propose the following three Specific Aims. First, we will test the hypothesis that the formation of a functional Na/K-ATPase/Src receptor complex requires a pair of interactions involving the Na/K-ATPase a, A-domain/Src SH2 domain, and the a, N-domain/Src kinase domain. Second, we will develop and employ cell permeable Na/K-ATPase-specific Src inhibitors/activators to test the hypothesis that activation of the Na/K-ATPase/Src receptor is responsible for the pharmacological/signaling actions of ouabain in the heart. Finally, we will employ genetically modified animal models to further evaluate the functionality of the Na/K-ATPase/Src receptor complex in the heart. The results of these studies will provide new insights into the molecular mechanism of Na/K-ATPase-mediated signal transduction and digitalis pharmacology. Moreover, with a better understanding of these new cellular signaling mechanisms, new targets for developing effective therapeutic interventions for the treatment or prevention of human diseases, including cardiac dysfunctions, may be established.
We have discovered a new cellular receptor Na/K-ATPase/Src complex that plays an important role in regulation of cellular activities in cardiac as well as other tissues. Understanding the molecular mechanism by which this newly discovered receptor operates will help us in developing more effective therapeutics for the treatment of cardiovascular and other diseases.
|Duan, Qiming; Xu, Yunhui; Marck, Pauline V et al. (2018) Preconditioning and Postconditioning by Cardiac Glycosides in the Mouse Heart. J Cardiovasc Pharmacol 71:95-103|
|Duan, Qiming; Xu, Yunhui; Marck, Pauline et al. (2017) Pre- and Post-conditioning by Cardiac Glycosides in the Mouse Heart. J Cardiovasc Pharmacol :|
|Morrill, Gene A; Kostellow, Adele B; Liu, Lijun et al. (2016) Evolution of the ?-Subunit of Na/K-ATPase from Paramecium to Homo sapiens: Invariance of Transmembrane Helix Topology. J Mol Evol 82:183-98|
|Wu, Jian; Li, Daxiang; Du, Lingling et al. (2015) Ouabain prevents pathological cardiac hypertrophy and heart failure through activation of phosphoinositide 3-kinase ? in mouse. Cell Biosci 5:64|
|Duan, Qiming; Madan, Namrata D; Wu, Jian et al. (2015) Role of phosphoinositide 3-kinase IA (PI3K-IA) activation in cardioprotection induced by ouabain preconditioning. J Mol Cell Cardiol 80:114-25|
|Mehta, Gaurav; Kumarasamy, Sivarajan; Wu, Jian et al. (2015) MITF interacts with the SWI/SNF subunit, BRG1, to promote GATA4 expression in cardiac hypertrophy. J Mol Cell Cardiol 88:101-10|
|Akkuratov, Evgeny E; Wu, Jian; Sowa, David et al. (2015) Ouabain-Induced Signaling and Cell Survival in SK-N-SH Neuroblastoma Cells Differentiated by Retinoic Acid. CNS Neurol Disord Drug Targets 14:1343-9|
|Li, Caixia; Culver, Silas A; Quadri, Syed et al. (2015) High-fat diet amplifies renal renin angiotensin system expression, blood pressure elevation, and renal dysfunction caused by Ceacam1 null deletion. Am J Physiol Endocrinol Metab 309:E802-10|
|Balasubramanian, Priya; Varde, Pratibha A; Abdallah, Simon Labib et al. (2015) Differential effects of prenatal stress on metabolic programming in diet-induced obese and dietary-resistant rats. Am J Physiol Endocrinol Metab 309:E582-8|
|Gable, Marjorie E; Abdallah, Simon L; Najjar, Sonia M et al. (2014) Digitalis-induced cell signaling by the sodium pump: on the relation of Src to Na(+)/K(+)-ATPase. Biochem Biophys Res Commun 446:1151-4|
Showing the most recent 10 out of 247 publications