Regulation of Na,K-ATPase activity.

The sodium pump Na,K-ATPase, a heterodimer of an alpha catalytic subunit and a beta glycoprotein subunit, is regulated by a wide array of hormonal, autocrine, and paracrine factors. Both short-term acute adjustments of activity and long-term adjustments of sodium pump pool size are important determinants of cellular Na,K-ATPase activity. Phosphorylation and dephosphorylation are implicated in the acute regulation of activity. Although there is not yet any direct demonstration of phosphorylation in vivo, in vitro studies on purified enzyme directly demonstrate that phosphorylation decreases Na,K-ATPase activity. In addition, it is likely that phosphorylation of other proteins regulates sodium pump activity and cellular distribution. In regard to long-term regulation, recent demonstration of differential translatability of alpha and beta mRNAs and differential stability of newly synthesized alpha and beta subunits suggests that beta subunit is synthesized in excess over alpha subunit and that the excess is rapidly degraded. The isoform composition of alpha beta heterodimers has been shown to affect enzymatic properties, and tissue-specific heterodimer patterns are emerging from regulation studies. In regard to Na,K-ATPase and hypertension, there is continued interest in the significance of the uncoupling of dopamine inhibition of proximal tubule Na,K-ATPase activity in hypertensive rat strains. The uncoupling has been shown to be specific to the proximal tubule, which has been shown to express DA1 dopamine receptors, and both receptor and postreceptor defects are implicated. Questions remaining include how activation of dopamine receptors is coupled to decreased sodium transporter expression in the proximal tubule (short- and long-term regulation) in normotensive rats, the precise nature of the defect in hypertension, and whether a similar defect is observed in human hypertensive patients.