The Na/K-ATPase-mediated signal transduction as a target for new drug development. Front Biosci

Department of Pharmacology and Medicine, Medical College of Ohio, Toledo, OH 43614, USA.
Frontiers in Bioscience (Impact Factor: 3.52). 02/2005; 10(1-3):3100-9. DOI: 10.2741/1766
Source: PubMed


The Na/K-ATPase, or Na+ pump, is a member of the P-type ATPase superfamily. In addition to pumping ions, the Na/K-ATPase is a receptor that not only regulates the function of protein kinases, but also acts as a scaffold, capable of tethering different proteins into a signalplex. The signaling Na/K-ATPase resides in caveolae and forms a "binary receptor" with the tyrosine kinase Src. Endogenous cardiotonic steroids and digitalis drugs such as ouabain act as agonists and provoke this binary receptor, resulting in tyrosine phosphorylation of the proteins that are either associated with, or in close proximity to, the signaling Na/K-ATPase. Subsequently, this initiates protein kinase cascades including ERKs and PKC isozymes. It also increases mitochondrial production of reactive oxygen species (ROS) and regulates intracellular calcium concentration. Like other receptors, activation of the Na/K-ATPase/Src by ouabain induces the endocytosis of the plasma membrane Na/K-ATPase. Significantly, this newly appreciated signaling function of the Na/K-ATPase appears to play an important role in the pathogenesis of many cardiovascular diseases, therefore serving as an important target for development of novel therapeutic agents.

Full-text preview

Available from:
  • Source
    • "Ouabain is a cardiotonic steroid that is primarily known as a plant-derived chemical that specifically binds to the Na+/K+-ATPase to modulate the ion transport function of the pump [32]–[44]. Recent research has established that ouabain and other cardiotonic steroids are in fact a newly discovered group of endogenous steroid hormones that are produced primarily by the adrenal glands [32]–[44]. This discovery has directed research towards understanding the physiological roles of endogenous cardiotonic steroids in regulating Na+/K+-ATPase function [32]–[44]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The Na(+)/K(+)-ATPase plays a pivotal role during preimplantation development; it establishes a trans-epithelial ionic gradient that facilitates the formation of the fluid-filled blastocyst cavity, crucial for implantation and successful pregnancy. The Na(+)/K(+)-ATPase is also implicated in regulating tight junctions and cardiotonic steroid (CTS)-induced signal transduction via SRC. We investigated the expression of SRC family kinase (SFK) members, Src and Yes, during preimplantation development and determined whether SFK activity is required for blastocyst formation. Embryos were collected following super-ovulation of CD1 or MF1 female mice. RT-PCR was used to detect SFK mRNAs encoding Src and Yes throughout preimplantation development. SRC and YES protein were localized throughout preimplantation development. Treatment of mouse morulae with the SFK inhibitors PP2 and SU6656 for 18 hours resulted in a reversible blockade of progression to the blastocyst stage. Blastocysts treated with 10(-3) M ouabain for 2 or 10 minutes and immediately immunostained for phosphorylation at SRC tyr418 displayed reduced phosphorylation while in contrast blastocysts treated with 10(-4) M displayed increased tyr418 fluorescence. SFK inhibition increased and SFK activation reduced trophectoderm tight junction permeability in blastocysts. The results demonstrate that SFKs are expressed during preimplantation development and that SFK activity is required for blastocyst formation and is an important mediator of trophectoderm tight junction permeability.
    Full-text · Article · Aug 2011 · PLoS ONE
  • Source
    • "Low concentrations of the CTS ouabain trigger signaling cascades in various cells [14] [15] that in many cases lead to the activation of Erk1/2. Thus, in order to investigate whether ouabain induces similar signaling events in the Sertoli cell line 93RS2, cells were incubated with various concentrations of ouabain for 30 min and cell lysates were isolated and investigated in western blots for Erk1/2 activation. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The α4 isoform of the Na(+),K(+)-ATPase (sodium pump) is known to be expressed in spermatozoa and to be critical for their motility. In the investigation presented here, we find that the rat-derived Sertoli cell line 93RS2 also expresses considerable amounts of the α4 isoform in addition to the α1 isoform. Since Sertoli cells are not motile, one can assume that the function of the α4 isoform in these cells must differ from that in spermatozoa. Thus, we assessed a potential involvement of this isoform in signaling pathways that are activated by the cardiotonic steroid (CTS) ouabain, a highly specific sodium pump ligand. Treatment of 93RS2 cells with ouabain leads to activation of the c-Src/c-Raf/Erk1/2 signaling cascade. Furthermore, we show for the first time that the activation of this cascade by ouabain results in phosphorylation and activation of the transcription factor CREB. This signaling cascade is induced at low nanomolar concentrations of ouabain, consistent with the involvement of the α4 isoform. This is further supported by experiments involving siRNA: silencing of α4 expression entirely blocks ouabain-induced activation of Erk1/2 whereas silencing of α1 has no effect. The findings of this study unveil new aspects in CTS/sodium pump interactions by demonstrating for the first time ouabain-induced signaling through the α4 isoform. The c-Src/c-Raf/Erk1/2/CREB cascade activated by ouabain is identical to the so-called non-classical signaling cascade that is normally triggered in Sertoli cells by testosterone. Taking into consideration that CTS are produced endogenously, our results may help to gain new insights into the physiological mechanisms associated with male fertility and reproduction.
    Preview · Article · Jul 2011 · Biochimica et Biophysica Acta
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In this review, we will discuss how proteinaceous water channels, termed aquaporins (AQPs), regulate water fluxes across plasma membranes within various physiological and pathophysiological contexts. Particular emphasis has been assigned to changes in aquaporin expression in brain matter in response to conditions where oxygen deprivation, such as hypoxia or ischemia, has been experimentally induced. We also discuss the specific role AQPs play in apoptosis, also known as programmed cell death, with special interest paid to AQPs in conjunction with potassium channels, and their seemingly interdependent function in regulating downstream apoptotic cascades. Finally, we argue for the possibility of connected aquaporin and potassium channel translocation during apoptotic insults.
    Full-text · Article ·
Show more