The cardiac sodium pump: structure and function

Cardiac sodium pumps (Na,K-ATPase) influence cell calcium and contractility by generating the Na+ gradient driving Ca++ extrusion via the Na+/Ca++ exchanger (NCX), and are the receptors for cardiac glycosides such as digitalis which increases cardiac contractility by decreasing the Na+ gradient driving Ca++ extrusion. There are multiple isoforms of the sodium pump expressed in the heart indicating the potential for isoform specific expression patterns, function and regulation. Regarding isoform expression patterns, human heart expresses alpha1, alpha2, alpha3, beta1 and a small amount of beta2. Within the human heart, alpha3, beta1 and NCX levels are 30-50% lower in atria than ventricles, associated with increased sensitivity to inotropic stimulation. Distribution at the cellular level has been studied in the rat heart where both alpha1 and alpha2 are detected in the T-tubules along with NCX. Regarding isoform function, we focussed on human sodium pumps as cardiac glycoside receptors. A study of human sodium pump expressed alone (alpha1) or in combination (alpha1 with alpha2, or alpha1 with alpha2 and alpha3) in their native membranes aimed to determine whether different isoforms had distinct affinities for the cardiac glycoside ouabain by evaluating whether the ouabain binding data were best fit with a single site or two site model. The results indicated that the affinity of these human a subunit isoforms for ouabain is indistinguishable, and that changes in sensitivity to cardiac glycosides during heart failure are likely due to a decrease in the total number of pumps rather than a shift in expression to a more sensitive isoform. Regarding isoform regulation, we hypothesized that a primary decrease in cardiac Na,K-ATPase expression would be associated with a secondary increase in cardiac Na+/Ca++ exchanger expression as a homeostatic mechanism to blunt an increase in cell Ca++ stores (and visa versa with an increase in Na,K-ATPase). Supporting the hypothesis: in a rat model of renovascular hypertension, or after treatment with amiodarone there are 50% decreases in alpha2 levels with 35-40% increases in NCX levels in left ventricle, while in the transition from hypo- to hyperthyroid, there are increases in both alpha1 (2-fold) and alpha2 (8-fold) with decreases in NCX (0.45-fold). In comparison, in transgenic mice overexpressing NCX, there was no secondary change in Na,K-ATPase alpha1 or alpha2 levels indicating that primary changes in NCX do not drive secondary changes in Na,K-ATPase in the heart. This information provides the basis for addressing the significant gaps in our understanding of the physiologic, structural and homeostatic coupling between sodium pump isoforms and Na+/Ca++ exchangers in the heart and how coupling is related to control of cardiac contractility in health and disease.