Identification of a specific role for the Na,K-ATPase alpha 2 isoform as aregulator of calcium in the heart

It is well accepted that inhibition of the Na,K-ATPase in the heart, throug h effects on the Na/Ca exchanger, raises the intracellular Ca2+ concentrati on and strengthens cardiac contraction. However, the contribution that indi vidual isoforms make to this calcium regulatory role is unknown. Assessing the phenotypes of mouse hearts with genetically reduced levels of Na,K-ATPa se alpha 1 or alpha 2 isoforms clearly demonstrates different functional ro les for these isoforms in vivo. Heterozygous (alpha 2 hearts are hypercontr actile as a result of increased calcium transients during the contractile c ycle. In contrast, heterozygous alpha 1 hearts are hypocontractile. The dif ferent functional roles of these two isoforms are further demonstrated sinc e inhibition of the alpha 2 isoform with ouabain increases the contractilit y of heterozygous alpha 1 hearts. These results definitively illustrate a s pecific role for the (alpha 2 Na,K-ATPase isoform in Ca2+ signaling during cardiac contraction.