Abstract
The signaling function of the Na/K-ATPase has been established for 20 years and is widely accepted in the field, with many excellent reports and reviews not cited here. Even though there is debate about the underlying mechanism, the signaling function is unquestioned. This short review looks back at the evolution of Na/K-ATPase signaling, from stimulation by cardiotonic steroids (also known as digitalis-like substances) as specific ligands to stimulation by reactive oxygen species (ROS) in general. The interplay of cardiotonic steroids and ROS in Na/K-ATPase signaling forms a positive-feedback oxidant amplification loop that has been implicated in some pathophysiological conditions.
Highlights
The data from this study indicates that increased [Na+]i is not the main cause of ouabain-induced Ca2+ oscillations, but rather the release of the α1 NH2 terminus during the Na/K-ATPase E1 to E2 conformational change serves as a mean of α1/IP3Rs complex formation
In primary cultures of cardiac myocytes, it was demonstrated that partial inhibition of Na/K-ATPase by ouabain stimulated c-Src- and Ras-dependent signaling which lead to mitochondrial KATP channel-related reactive oxygen species (ROS) generation, and that ouabain-induced cardiac hypertrophic growth involved ROS-dependent signaling pathways [6]
Pretreatment with antioxidant N-acetyl-L-cysteine (NAC) or disruption of the Na/K-ATPase/c-Src signaling complex attenuated ouabain- and glucose-oxidase-stimulated Na/K-ATPase/c-Src signaling, protein carbonylation, redistribution of Na/K-ATPase, and inhibition of active transepithelial 22Na+ transport. This indicated that ROS are critical in initiating ouabain-stimulated Na/K-ATPase/c-Src signaling, and carbonylation modification of the α1 subunit is involved in a feed-forward mechanism of regulation of ouabain-mediated Na/K-ATPase signal function and subsequent Na+ transport
Summary
Ouabain-stimulated Na/K-ATPase signaling increases the generation of ROS, which functions as a second messenger. Ouabain-stimulated activation of the Na/K-ATPase signaling function increases mitochondrial ROS generation that functions as an essential second messenger [6,11]. In primary cultures of cardiac myocytes, it was demonstrated that partial inhibition of Na/K-ATPase by ouabain stimulated c-Src- and Ras-dependent signaling which lead to mitochondrial KATP channel-related ROS generation, and that ouabain-induced cardiac hypertrophic growth involved ROS-dependent signaling pathways [6].
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