Hypokalemia decreases Na(+)-K(+)-ATPase alpha 2- but not alpha 1-isoform abundance in heart, muscle, and brain

Abstract

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.(ABSTRACT TRUNCATED AT 250 WORDS)

K + -dependent paradoxical membrane depolarization and Na + overload, major and reversible contributors to weakness by ion channel leaks

“…Possible compensatory overexpression of the Na/K-ATPase may be expected; however, quantitative RT-PCR suggests that the opposite, a reduction in the ␣2 subunit, occurs, similar to the functional decrease in leaky neurons (13). The reduced ATPase expression is similar to that of the K-depleted rat model of HypoPP (23). Reduced ATPase may indicate that serum K ϩ levels need to be maintained by limiting transport into cells.…”

“…Two experienced radiologists determined ROI by consensus. For both 23 Na and 1 H broadband measurements, a unique double-resonant birdcage coil was used (Rapid Biomed).…”

“…The first is an examination of [Na ϩ ] i overload and muscle weakness as clinical signs of a pathologic cation leak in the model disorder HypoPP. Thirty-six patients volunteered for the study, all of whom were examined by new 23 Na MRI (15). Seven of the patients consented to muscle biopsy to measure K ϩ -dependent membrane potential distribution and leaks.…”

Changes in the expression of Na+/K+-ATPase isoenzymes in the left ventricle of diabetic rat hearts: effect of insulin treatment

“…It is well documented that aldosterone alone is sufficient to induce alpha 1 and beta I gene expression in cardiomyocytes [42]. In hypokalaemia, alpha 2 isoform expression is depressed in the heart [11]. In the heart, it is mainly the alpha 2 and beta I mRNA level that is influenced by hypothyroid state [43,44].…”

“…Three isoforms of the beta subunit have also been described [10]. Although significance of the tissue-and cell-specific distribution of the subunit isoforms is not known, evidence is accumulating that alpha subunit isoforms may be differentially regulated by physiological and pathological stimuli [11,12].…”