Hypercholesterolemia induces up-regulation of K _ACh cardiac currents via a mechanism independent of phosphatidylinositol 4,5-bisphosphate and Gβγ

Hypercholesterolemia is a well-known risk factor for cardiovascular disease. In the heart, activation of K _ACh mediates the vagal (parasympathetic) negative chronotropic effect on heart rate. Yet, the effect of cholesterol on K _ACh is unknown. Here we show that cholesterol plays a critical role in modulating K _AChcurrents (I _K,ACh) in atrial cardiomyocytes. Specifically, cholesterol enrichment of rabbit atrial cardiomyocytes led to enhanced channel activity while cholesterol depletion suppressed I _K,ACh. Moreover, a high-cholesterol diet resulted in up to 3-fold increase in I _K,ACh in rodents. In accordance, elevated currents were observed in Xenopus oocytes expressing the Kir3.1/Kir3.4 heteromer that underlies I _K,ACh. Furthermore, our data suggest that cholesterol affects I _K,ACh via a mechanism which is independent of both PI(4,5)P ₂ and Gβγ. Interestingly, the effect of cholesterol on I _K,ACh is opposite to its effect on I _K1 in atrial myocytes. The latter are suppressed by cholesterol enrichment and by high-cholesterol diet, and facilitated following cholesterol depletion. These findings establish that cholesterol plays a critical role in modulating I _K,ACh in atrial cardiomyocytes via a mechanism independent of the channel's major modulators.