The Na$^+$/K$^+$-ATPase alpha2-isoform regulates cardiac contractility in rat cardiomyocytes.
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Cardiovasc. Res. 75 (1): 109--117 (July 2007)

OBJECTIVE: The presence of both alpha1- and alpha2-isoforms of the Na$^+$/K$^+$-ATPase (NKA) in cardiomyocytes indicates different functions. We hypothesized that preferential localization of the alpha2-isoform to the t-tubules, locally controlling the Na$^+$/Ca$^2+$-exchanger (NCX), underlies a specific role in Ca$^2+$ handling. METHODS: We studied NKA isoform distribution in isolated cardiomyocytes from Wistar rats using immunocytochemistry. NKA pump and NCX currents (I(pump) and I(NCX)) were measured in control and detubulated cardiomyocytes. Intracellular Na$^+$ concentration Na$^+$i was assessed with the fluorescent dye SBFI. RESULTS: The alpha2-isoform abundance was higher in the t-tubules than in the surface sarcolemma. We established that 0.3 microM ouabain specifically blocked the alpha2-isoform in isolated rat cardiomyocytes. This low concentration blocked 10.7+/-0.6\% of I(pump) in control, but only 6.0+/-0.5\% in detubulated cardiomyocytes. Moreover, measured and calculated alpha1-specific and alpha2-specific I(pump) in control (547+/-29 pA and 66 pA, respectively) and in detubulated cells (495+/-30 pA and 31 pA, respectively) showed that 53\% of the alpha2-isoform, but only 9.5\% of the alpha1-isoform, were localized to the t-tubules. Despite the small abundance of the alpha2-isoform (approximately 11\% of total NKA), selective inhibition of this isoform induced a 40\% increase in contractility in field stimulated cardiomyocytes, but no increase in global Na$^+$i. However, inhibition of the alpha2-isoform increased I(NCX) indicating local subsarcolemmal accumulation of Na$^+$ near NCX. CONCLUSIONS: The alpha2-isoform of the NKA is functionally coupled to the NCX and can regulate Ca$^2+$ handling without changing global Na$^+$i.
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