We study the function and regulation of ion transporters with strong interests in both biophysical and cell biological questions. We are especially interested in the processes of membrane fusion and endocytosis as mechanisms that can regulate the presence of ion transporters in the cell surface. The ion transporters we study include the cardiac Na/Ca exchange system, the Na/K pump, and Na/H exchangers. All three play key roles in cardiac physiology and pathology. Over the years, we have developed a number of new methods that have facilitated our analyses of these systems. Our methods allow us to study conformational changes of transport proteins with one microsecond resolution, allow us to study ion transport independent of membrane electrical currents, and they allow us to study directly the insertion and retrieval of membrane at the cell surface with high resolution and with unprecedented control of the composition of the cytoplasm. We recently discovered that phosphatidylinositides are important regulators of ion transporters and channels, while at the same time they control the membrane trafficking events that move transporters out of the cell surface. We are now studying how enzymes involved in phosphatidylinositide regulate in parallel ion transport activities and membrane trafficking.
These projects are highly relevant to cardiovascular disease, which is still the leading cause of death in the United States. Many deaths in the immediate aftermath of myocardial infarction are caused by cardiac arrhythmias. In the long-term of cardiac insufficiency, changes of cardiac excitation-contraction coupling and associated arrhythmias are known to play an important role in time course and severity of developing cardiac dysfunction. The pathogenesis of arrhythmias is complex and involves numerous molecular entities. The cardiac Na/Ca exchanger, which removes Ca from cardiac myocytes is our major focus, is thought to play a trigger role in many cases by generating depolarizing membrane currents. Also, this transporter is implicated to mediate much cardiac cell damage from ischemia-reperfusion episodes by loading cardiac cells with calcium in response to previous Na loading, thereby causing myocyte hypercontraction and promoting cell death programs to be activated via mitochondrial signaling mechanisms that are set in motion. The endocytic mechanisms we are studying, which remove this transporter from the cell surface, have been found to be activated in response to ischemia and/or oxygen deprivation. Over many years we have developed extensive simulations of cardiac ion transport and electrophysiology that now can be used to help to understand pathological changes of cardiac function in the short- and long-term of cardiac disease affecting cardiac artery perfusion and function.
RESEARCH INTERESTS
Membrane transport mechanisms
Lipid Signaling
Electrophysiology
Calcium Signaling
RECENT PUBLICATIONS
Hilgemann DW, "New insights into the molecular and cellular workings of the cardiac Na+/Ca2+ exchanger." Am J Physiol Cell Physiol, 287(5):C1167-72, November 2004
Hilgemann DW, Yaradanakul A, Wang Y, Fuster D, "Molecular control of cardiac sodium homeostasis in health and disease." J Cardiovasc Electrophysiol, 17 Suppl 1:S47-S56, May 2006
Daniel Fuster, Orson Moe and Donald W. Hilgemann, "Steady State Function of the Ubiquitous Mammalian Na/H Exchanger (NHE1)" Journal of General Physiology, In Press October 2008
Yaradanakul A, Wang TM, Lariccia V, Lin MJ, Shen C, Liu X, Hilgemann DW, "Massive Ca-induced membrane fusion and phospholipid changes triggered by reverse Na/Ca exchange in BHK fibroblasts." J Gen Physiol., 132:29-50
Kang TM, Hilgemann DW., "Multiple transport modes of the cardiac Na+/Ca2+ exchanger" Nature, 427:544-546, October 2004
SIGNIFICANT PUBLICATIONS
Hilgemann DW, Lu C-C, "Giant membrane Patches: Improvements and Applications" Methods in Enzymology, 293:267-80, 1998
Hilgemann DW, Ball R, "Regulation of cardiac Na+,Ca2+ exchange and KATP potassium channels by PIP2" Science, 273(5277):956-9, 1996
Hilgemann DW, Feng S, Nasuhoglu C, "The complex and intriguing lives of PIP2 with ion channels and transporters" Sci STKE, 2001(111):RE19, December 2001
Hwang C, Feng Y, and Hilgemann DW, "Direct Interaction of PIP2 with inward rectifier potassium channels and its enhancement by G-beta-gamma" Nature, 391:803-06, 1998
Related Articles, LinksYaradanakul A, Feng S, Shen C, Lariccia V, Lin MJ, Yang J, Kang T M, Dong P, Yin HL, Albanesi JP, Hilgemann DW., "Dual control of cardiac Na+ Ca2+ exchange by PIP(2): electrophysiological analysis of direct and indirect mechanisms." The Journal of Physiology, 582:991-1010, June 2007
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