HYPOKALEMIA DECREASES NA+-K+-ATPASE ALPHA-2-ISOFORM BUT NOT ALPHA-1-ISOFORM ABUNDANCE IN HEART, MUSCLE, AND BRAIN

K+ deficiency has been linked to a loss of K+ from muscle associated with a decrease in ouabain binding and K+-dependent phosphatase activity. This study aimed to quantitate the Na+-K+-ATPase alpha- and beta-isoform-specific responses to hypokalemia in vivo in heart, skeletal muscle, and brain at pre- and posttranslational levels. Two-week dietary K+ restriction resulted in decreases in alpha-2-mRNA in heart and skeletal muscle to 0.60 and 0.65, and in alpha-2-protein abundance to 0.38 and 0.18 of control, respectively. The decrease in alpha-2-protein was greater than the decrease in mRNA in both tissues, suggesting translational and/or posttranslational mechanism(s) of regulation as well as pretranslational regulation in response to hypokalemia. K+-dependent p-nitrophenyl phosphatase (pNPPase) activity decreased in heart and skeletal muscle to 0.67 and 0.58, respectively. There were no changes in alpha-1- or beta-mRNA or protein levels in skeletal muscle or heart. In brain, there was a similar pattern of regulation. While brain alpha-2-mRNA did not change in hypokalemia, protein levels decreased to 0.72 of control. In conclusion, hypokalemia is associated with a large decrease in expression of the alpha-2-isoform of Na+-K+-ATPase. These results support the hypothesis that in skeletal and heart muscle hypokalemia induces a decrease in Na+-K+-ATPase activity (measured as K+-dependent pNPPase activity) by specifically decreasing the expression of the alpha-2-isoform of Na+-K+-ATPase. Because the majority of sodium pumps in muscle are of the alpha-2-isoform, this could lead to decreased reuptake of K+ into the muscle cells, effectively moving intracellular K+ into the extracellular fluids.