The Na/K-ATPase/Src complex and cardiotonic steroid-activated protein kinase cascades

Department of Physiology and Pharmacology, University of Toledo College of Medicine, Health Science Campus, Mail Stop 1008, 3000 Arlington Avenue, Toledo, OH 43614-2598, USA.
Pflügers Archiv - European Journal of Physiology (Impact Factor: 4.1). 03/2008; 457(3):635-44. DOI: 10.1007/s00424-008-0470-0
Source: PubMed


The Na/K-ATPase was discovered by Skou in 1957. Since then, the efforts of numerous investigators have led to the following conclusions: (a) This enzyme is indeed the molecular machine for the ATP-dependent and -coupled transport of Na(+) and K(+) across the plasma membrane of a living cell in which such a process (sodium pump) is detected. (b) The Na/K-ATPase is also an important signal transducer that not only interacts and regulates protein kinases, but also functions as a scaffold, capable of bringing the affector and effectors together to form functional signalosomes. This minireview discusses the interaction between the Na/K-ATPase and Src to illustrate how a P-type ATPase can act as a receptor, converting a ligand-binding signal to the activation of protein kinase cascades and the generation of second messengers.

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    • "A large body of evidence has accumulated suggesting that Na ϩ ,K ϩ - ATPase molecules are tightly packed with other integral proteins in functional clusters in the cell plasma membranes of different tissues. This provides direct molecule interplay and functional interaction between Na ϩ ,K ϩ -ATPase and neighboring proteins (Xie and Askari, 2002; Li and Xie, 2009). To look for the recipient of Na ϩ ,K ϩ -ATPase regulatory action in neurons we focused on the plasma membrane NCX, because it has been shown that these two molecules are anchored, forming a functional complex in the plasma membrane of cardiomyocytes (Xie and Askari, 2002; Aperia, 2007). "
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    ABSTRACT: Here, using a fluorescent viability assay, immunocytochemistry, patch-clamp recordings, and Ca(2+)-imaging analysis, we report that ouabain, a specific ligand of the Na(+),K(+)-ATPase cardiac glycoside binding site, can prevent glutamate receptor agonist-induced apoptosis in cultured rat cortical neurons. In our model of excitotoxicity, a 240 min exposure to 30 μM NMDA or kainate causes apoptosis in ~50% of neurons. These effects are accompanied by a significant decrease in the number of neurons that are immunopositive for the antiapoptotic peptide Bcl-2. Apoptotic injury is completely prevented when the agonists are applied together with 0.1 nM or 1 nM ouabain resulting in a greater survival of neurons and the percentage of neurons expressing Bcl-2 remains similar to those obtained without agonist treatments. In addition, subnanomolar concentrations of ouabain prevent the increase of spontaneous EPSC's frequency and the intracellular Ca(2+) overload induced by excitotoxic insults. Loading neurons with BAPTA or inhibition of the plasma membrane Na(+),Ca(2+)-exchanger by KB-R7943 eliminate ouabain effects on NMDA or kainate evoked enhancement of spontaneous synaptic activity. Our data suggest that during excitotoxic insults ouabain accelerates Ca(2+) extrusion from neurons via the Na(+),Ca(2+)-exchanger. Since intracellular Ca(2+) accumulation caused by the activation of glutamate receptors and the boosted synaptic activity represents a key factor in triggering neuronal apoptosis, up-regulation of Ca(2+) extrusion abolishes its development. These antiapoptotic effects are independent of the Na(+),K(+)-ATPase ion transport function and initiated by concentrations of ouabain that are within the range of an endogenous analog, suggesting a novel functional role of the Na(+),K(+)-ATPase in neuroprotection.
    Full-text · Article · Aug 2012 · Journal of Pharmacology and Experimental Therapeutics
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    • "Binding to these proteins not only regulates the ion-pumping function of the enzyme, but it also conveys signal-transducing functions to the Na/K-ATPase [18, 32, 37–39]. In LLC-PK1 cells, the Na/K-ATPase α1 subunit and Src form a functional receptor in which the binding of CTS to the α1 subunit activates Src and consequent signaling cascade [39]. The signaling function of the Na/K-ATPase regulates numerous cell functions in various types of organs and cells including cell motility, cell proliferation, cancer, endothelin release, glycogen synthesis, apoptosis, hypertension, intracellular calcium signaling, cardiac hypertrophy, cardiac remodeling, renal remodeling, epithelial cell tight junction, vascular tone homeostasis, and sodium homeostasis [26, 40–59]. "
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    ABSTRACT: The Na/K-ATPase is the primary force regulating renal sodium handling and plays a key role in both ion homeostasis and blood pressure regulation. Recently, cardiotonic steroids (CTS)-mediated Na/K-ATPase signaling has been shown to regulate fibrosis, renal proximal tubule (RPT) sodium reabsorption, and experimental Dahl salt-sensitive hypertension in response to a high-salt diet. Reactive oxygen species (ROS) are an important modulator of nephron ion transport. As there is limited knowledge regarding the role of ROS-mediated fibrosis and RPT sodium reabsorption through the Na/K-ATPase, the focus of this review is to examine the possible role of ROS in the regulation of Na/K-ATPase activity, its signaling, fibrosis, and RPT sodium reabsorption.
    Full-text · Article · Feb 2012
    • "The best analyzed receptor, EGF-R, is a tyrosinase kinase receptor, and its interaction with NKA in the signalosome is well established.[212426] EGF-R kinase domain mutants found in non-small cell lung cancer (NSCLC) are constitutively active, a trait critical for malignant cell transformation. "
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    ABSTRACT: Since their first discovery as potential anti-cancer drugs decades ago, there is increasing evidence that digitalis-like compounds (DLC) have anti-tumor effects. Less is known about endogenous DLC (EDLC) metabolism and regulation. As stress hormones synthesized in and secreted from the adrenal gland, they likely take part in the hypothalamo-pituitary-adrenal (HPA) axis. In a previous study, we revealed reduced EDLC concentrations in plasma and organs from immune-compromised animals and proposed that a similar situation of a deregulated HPA axis with "adrenal EDLF exhaustion" may contribute to tumorigenesis in chronic stress situations. Here, we put forward the hypothesis that a lowered EDLC response threshold of tumor cells as compared with normal cells increases the risk of tumorigenesis, especially in those individuals with reduced EDLC plasma concentrations after chronic stress exposure. We will evaluate this hypothesis by (a) summarizing the effects of different DLC concentrations on tumor as compared with normal cells and (b) reviewing some essential differences in the Na/K-ATPase of tumor as compared with normal cells (isoform pattern, pump activity, mutations of other signalosome receptors). We will conclude that (1) tumor cells, indeed, seem to have their individual "physiologic" EDLC response range that already starts at pmolar levels and (2) that individuals with markedly reduced (pmolar) EDLC plasma levels are predisposed to cancer because these EDLC concentrations will predominantly stimulate the proliferation of tumor cells. Finally, we will summarize preliminary results from our department supporting this hypothesis.
    No preview · Article · Feb 2012 · Journal of Carcinogenesis
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