North Shore Heart Research Laboratory
Head of laboratory
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Overview of research program
Oxidative signaling: a key mechanism of Na-K pump regulation
Our group was established by Helge Rasmussen in 1988 on his return from a Fellowship at Chicago’s Northwestern Memorial Hospital. The laboratory is recognised internationally for its expertise in cellular electrophysiology, in particular using whole cell patch clamp techniques for measuring Na+-K+ pump activity in isolated cardiac myocytes. We are particularly interested in the Na+-K+ pump because of its critical role in establishing electrochemical gradients, as well as determining intracellular Na+ concentration in the myocyte. These factors are important in heart failure, a condition in which raised intracellular Na+ levels are associated with impaired cardiac contractility, and increased arrhythmias. Despite its discovery more than 60 years ago, the regulation of the Na+-K+ pump remains poorly understood.
Recent electrophysiology studies by the group have suggested the role of oxidative signalling in the regulation of the cardiac Na+-K+ pump. Our current focus is to further characterise this, and to identify the molecular mechanism by which an oxidative signal may modify the activity of the pump molecule. We have investigated the hypothesis that direct oxidative modification of the pump molecule mediates its acute regulation. Our initial work examined for the presence of S-glutathionylation of Na+-K+ pump subunits expressed in the heart. This form of oxidative modification, which occurs in the presence of the abundant cellular tripeptide glutathione, is a good candidate for cellular signalling as it results in the addition of a 305 Da, negatively charged group to susceptible sulfhydryl groups on signalling proteins. This has the potential to induce steric effects on protein function similar to phosphorylation. We have identified glutathionylation of the β1 subunit of the Na+-K+ pump, which increased in response to chemical oxidants. Future work will investigate the significance of this modification, and its role in mediating the oxidative-dependent regulation of the pump by hormones. Heart failure is characterised by raised intracellular oxidant stress, raised intracellular Na+, and dysregulation of neurohormones. It is therefore crucial to establish details of the mechanism by which neurohormones regulate the Na+-K+ pump by ROS/RNS. Understanding these interactions could provide new targets for pharmacological treatment.
Major funding sources
- North Shore Heart Research Foundation
- Royal Australian College of Physicians
- National Health and Medical Research Council
Selected publications
William, M., Hamilton, E.J., Garcia, A., Bundgaard, H., Figtree, G.A., H.H. Rasmussen. Natriuretic peptides stimulate the cardiac sodium pump via NPR-C coupled NOS activation. Am J Physiol (Cell Physiol), 2008 Apr;294(4):C1067-73.
White, C., Hamilton, E., Garcia, A., Wang, D., Chia, K., Figtree, G., Rasmussen, H. Opposing effects of coupled and uncoupled NOS activity on the Na+-K+ pump in cardiac myocytes. American journal of physiology. Cell physiology. 2008; 294:C572-8.
Rasmussen, H., Figtree, G. "Don't flog the heart!" - development of specific drug therapies for heart failure. Critical care and resuscitation : journal of the Australasian Academy of Critical Care Medicine. 2007; 9:364-369.
Hansen, P., Clarke, R., Buhagiar, K., Hamilton, E., Garcia, A., White, C., Rasmussen, H. Alloxan-induced diabetes reduces sarcolemmal Na+-K+ pump function in rabbit ventricular myocytes. American journal of physiology. Cell physiology. 2007; 292:C1070-7.
White, C., Hamilton, E., Garcia, A., Rasmussen, H. PKA inhibits the Na+-K+ pump in cadiac myocytes via superoxide. Journal of Molecular and Cellular Cardiology. 2006; 41:744-745.
William, M., Vien, J., Hamilton, E., Garcia, A., Bundgaard, H., Clarke, R., Rasmussen, H. The nitric oxide donor sodium nitroprusside stimulates the Na+-K+ pump in isolated rabbit cardiac myocytes. The Journal of physiology. 2005; 565:815-25.
Buhagiar, K., Hansen, P., Kong, B., Clarke, R., Fernandes, C., Rasmussen, H. Dietary cholesterol alters Na+/K+ selectivity at intracellular Na+/K+ pump sites in cardiac myocytes. American journal of physiology. Cell physiology. 2004; 286:C398-405.
Major collaborations
- Dr Ron Clarke (University of Sydney, Australia)
- Associate Professor Francesca Marassi (Burnham Institute for Medical Research, USA)
- Professor Kaethi Geering and Stephanie Bibert (University of Lausanne, Switzerland)
- Dr Flemming Cornelius (Institute of Physiology and Biophysics, Denmark)
