Irena Levitan
University of Illinois at Chicago, USA
Title: Impact of hypercholesterolemia on cardiac K+ channels
Biography
Biography: Irena Levitan
Abstract
Plasma hypercholesterolemia is well known to be a major risk factor for the development of cardiovascular disease. Our studies focus on the impact of cholesterol on two types of inwardly-rectifying K+ channels expressed in cardiomyocytes: classical inward rectifiers Kir channels (Kir2) that play a major role in maintaining cardiac membrane potential and G-protein gated Kir (GIRK or Kir3) channels that play an important role in the regulation of atrial action potential. Paradoxically, our studies show that elevation of membrane cholesterol in vitro and in vivo has opposite effects on Kir2 and Kir3 channels in the same cells. Specifically, enriching cardiomyocytes with cholesterol in vitro suppresses the activity of Kir2 channels but enhances the activity of Kir3 channels. Furthermore, plasma dyslipidemia in vivo also have opposite effects on these channels in freshly-isolated cardiomyocytes. Both effects are mediated by a decrease or increase in the open probability of Kir2 and Kir3 respectively. Even more surprising, even though cholesterol has opposite effects on the function of Kir2 and Kir3, both effects are abrogated by a specific mutation indicating that they share some structural determinants. These studies are discussed in terms of the structural-mechanistic insights into cholesterol regulation of Kir channels and in terms of the physiological/pathological impact of these coupled effects on cardiac function.
