The Physiological Significance of the Cardiotonic Steroid/Ouabain-Binding Site of the Na,K-ATPase

Abstract

The Na,K-ATPase is the membrane "pump" that generates the Na + and K + gradients across the plasma membrane that drives many physiological processes. This enzyme is highly sensitive to inhibition by cardiotonic steroids, most notably the digitalis/ouabain class of compounds, which have been used for centuries to treat congestive heart failure and arrhythmias. The amino acids that constitute the ouabain-binding site are highly conserved across the evolutionary spectrum. This could be fortuitous or could result from this site being conserved because it has an important biological function. New physiological approaches using genetically engineered mice are being used to define the biological significance of the "receptor function" of the Na,K-ATPase and its regulation by potential endogenous cardiotonic steroid-like compounds. These studies extend the reach of earlier studies involving the biochemical purification of endogenous regulatory ligands.

The impaired intestinal mucosal immune system by valine deficiency for young grass carp (Ctenopharyngodon idella) is associated with decreasing immune status and regulating tight junction proteins transcript abundance in the intestine

“…In zebrafish (Danio rerio) intestinal epithelial cells, up-regulated Claudin 15 expression could increase extracellular Na þ concentrations [81]. Moreover, Na þ , K þ -ATPase which is located on the basolateral membrane, can transport Na þ out of cells [82]. In the fish intestine, valine-deficient diet and valine-excessive diet were found to decreased Na þ , K þ -ATPase activity [8].…”

“…In the fish intestine, valine-deficient diet and valine-excessive diet were found to decreased Na þ , K þ -ATPase activity [8]. Lingrel [82] indicated that the homeostasis of Na þ ions in the intestinal epithelial cells is an important guarantee for its function. Thus, high gene expression of Claudin 15 in valine-deficient diet and valine-excessive diet may be an adaptation to the intestinal function in this study, but the underlying mechanism needs to be further investigated.…”

Subunit Isoform Selectivity in Assembly of Na,K-ATPase α-β Heterodimers

“…The Na,K-ATPase is universally expressed in all animal cells where it generates electrochemical ion gradients that are critical for many cellular processes (1)(2)(3). The Na,K-ATPase is composed of two essential subunits, ␣ and ␤.…”

“…The ␣ 2 isoform is expressed mainly in muscle and nervous system (1-3, 6, 7); the ␣ 3 isoform is expressed mainly in neurons (8,9), whereas the ␣ 4 isoform is found only in testis (10,11). The ␤ 2 isoform is expressed predominantly in brain and muscle (3,7), whereas the ␤ 3 isoform is mainly expressed in lung, testis, skeletal muscle, and liver (12,13). The ␣ 2 isoform regulates contractility of cardiac, smooth, and skeletal muscle and plays a key role in the modulation of blood pressure in response to stress (3,14,15).…”

Active ingredients in Chinese medicines promoting blood circulation as Na+/K+-ATPase inhibitors

“…Specifically, the ability of Na + /K + -ATPase to establish and maintain ion gradients makes it essential for the generation and maintenance of electrical membrane potentials, which are necessary for neuronal excitability, transmission [19] and cardiac muscle contraction [20] . Na + /K + -ATPase also generates the Na + gradient that is critical for the reabsorption of sodium ion and water from the glomerular filtrate in the nephron [21] and absorption of fluid from the lungs and intestine [22] . It can also drive secondary active co-/countertransporters, which are coupled to the gradient of extracellular to intracellular Na + concentration, such as the sodium glucose cotransporter and the Na + /Ca 2+ exchanger [23] .…”