Coetzee Laboratory

Our overall objective is to study the role of ion translocating mechanisms (channels, exchangers and pumps) in health and disease. We utilize multi-disciplinary approaches that take advantage of several methodologies, including biochemistry, molecular biology, electrophysiology, subcellular imaging of ion concentrations with confocal microscopy and genetically altered animal model systems.

ATP-sensitive potassium channels as macromolecular complexes

KATP channels couple cellular metabolic status to membrane excitability, thereby contributing to the regulation of tissue responses to physiological and pathophysiological stimuli. We found that glycolytic enzymes associate with KATP channel subunits and weare currently examinig the hypothesis that glycolytic enzymes are integral components of the KATP channel macromolecular complex that regulate KATP channel activity under physiological and pathophysiological conditions. Protein interactions are being further investigated using advanced proteomic approaches (ICAT & ITRAQ), which has the potential to uncover additional novel KATP channel interacting proteins. As part of this project we are investigating the interaction of glycolysis and KATP channels in the context of ischemic protection in cardiac myocytes and the coronary vasculature, using genetic mouse models that express dominant-negative KATP channel subunits specifically in the cardiac myocyte, smooth muscle or endothelium.

Regulation of vascular function by KATP channels

We recently described a novel role for KATP channels to regulate vascular tone. We found that these channels regulate release of the vasoconstrictor, endothelin-1 from the endothelium and that increased ET-1 release is causatively involved in regulating blood pressure and coronary artery resistance. We are currently defining the molecular nature of the endothelial KATP channel and its electrophysiological characteristics. We also examine the role of endothelial KATP channels in controlling the membrane potential and intracellular Ca2+ (as mediators of endothelial cell function and ET-1 release). Additionally, we are performing studies to examine the roles of endothelial KATP channels during pathophysiological insults, such as changes in coronary flow during hypoxia and ischemia and the myocardial response and infarct size in response to ischemia/reperfusion.