The sodium pump and hypertension: A physiological role for the cardiac glycoside binding site of the Na,K-ATPase

Kaplan, Jack H.

doi:10.1073/pnas.0507965102

Cited by 19 publications

(10 citation statements)

References 27 publications

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“…On the other hand, cardiac glycosides were present in our extract as previously reported by Edeoga et al (2005) in a Nigerian plant sample. Plant extracts containing cardiac glycosides have been used for their therapeutic effects (Kaplan, 2005) but could be a source of toxicity (Demiryurek and Demiryurek, 2005).…”

Section: Staphylococcus Aureusmentioning

confidence: 99%

Antidiarrhoeal and antimicrobial activities of Emilia coccinea (Sims) G. Don extracts

Teke

Kuiaté

Ngouateu

et al. 2007

Journal of Ethnopharmacology

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Section: Staphylococcus Aureusmentioning

confidence: 99%

Antidiarrhoeal and antimicrobial activities of Emilia coccinea (Sims) G. Don extracts

Teke

Kuiaté

Ngouateu

et al. 2007

Journal of Ethnopharmacology

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“…It is known that CTS are elevated during volume expansion. The cardiotonic steroid binding site of the Na-K-ATPase is believed to be the molecular target of the hypertensive effects of these compounds, and appears to play an important role in blood pressure regulation [125,126]. Our recent in vivo studies have demonstrated that elevated endogenous CTS and endocytosis of the Na/K-ATPase play an important role in renal adaptation to volume expansion.…”

Section: Physiological Implicationsmentioning

confidence: 99%

Regulation of sodium pump endocytosis by cardiotonic steroids: Molecular mechanisms and physiological implications

Liu

Shapiro

2007

Pathophysiology

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We have previously shown that ouabain and other cardiotonic steroids interact with the plasmalemmal Na/K-ATPase and cause a time and dose dependent endocytosis of the Na/K-ATPase. This endocytosis is demonstrable using fluorescence imaging as well as conventional biochemical and biophysical cell separation methods. In proximal tubule cells, this process appears to regulate the density of basolateral Na/K-ATPase expression directly as well as indirectly modulate transepithelial sodium transport.Work with genetic manipulations, as well as pharmacological agents with cell culture models, have demonstrated that the cardiotonic steroid stimulated endocytosis of the plasmalemmal Na/K-ATPase requires caveolin and clathrin as well as the activation of c-Src, transactivation of the EGFR and activation of PI3K. Interestingly c-Src, EGFR and ERK1/2 all appear to be endocytosed along with the plasmalemmal Na/K-ATPase. These observations suggest a close analogy between a subset of plasmalemmal Na/K-ATPase and signaling companions with conventional receptor tyrosine kinases. While further studies are necessary to delineate the role of this endocytosis in the generation as well as the limit of signal transduction through the Na/K-ATPase signal cascade, we propose that it has an important role in the regulation of renal sodium handling as well as other important processes.

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“…It is the target of cardiac glycosides, such as digitalis, and the catalytic a subunit contains the glycoside binding site as well as the conserved aspartate residue that undergoes cyclic phosphorylation and dephosphorylation events that drive the conformational transitions underlying the operation of this P-type ion pump. Its activity maintains the transmembrane electrochemical alkali cation gradients that are coupled to the flux of other ions by a host of exchangers and cotransporters and that are dissipated by ion channels in the propagation of action potentials [Kaplan, 2002[Kaplan, , 2005Jorgensen et al, 2003]. It was therefore surprising that a disease phenotype as subtle, intermittent, and localized as FHM should be linked to mutations in ATP1A2, encoding the a2 isoform of the major subunit of this mechanism [De Fusco et al, 2003;Kaunisto et al, 2004].…”

Section: Pathophysiology Of Fhmmentioning

confidence: 99%

Monogenic migraine syndromes highlight novel drug targets

Gargus

Shih

2007

Drug Development Research

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In the post‐genomic era, the paradigm for drug discovery has changed, as every gene may become a potential target. Genetic diseases provide a special window into gene target selection. This approach is being applied to migraine making use of the genes and mutations causing familial hemiplegic migraine (FHM). FHM is caused by missense mutations in CACNA1A, altering a neuronal P/Q Ca2+ channel, in ATP1A2, altering α2 Na,K‐ATPase, and in SCN1A, altering a neuronal sodium channel. These genes provide insights into migraine pathogenesis that likely extend to other forms of migraine as well. Since the three FHM genes are only co‐expressed in neurons, FHM is a neuronal, not a vascular, disease and because they all encode ion transport proteins, FHM is a neuronal channelopathy—meaning meta‐stable neuronal hyperexcitability is the substrate of migraine, much as it is for genetic epilepsy syndromes. This similarity is reinforced, since different mutations of all three FHM genes can produce seizure syndromes. This has implications for drug discovery in that seizure medications already known to modulate the FHM channel mechanisms warrant more targeted development, and that drugs targeted to vascular headaches, such as the historically effective triptans, or experimental botulinum toxin, may well work by similar nonvascular mechanisms. Finally, in model neurogenetic systems such as Caenorhabditis elegans, the FHM genes also provide both a comprehensive means to discover all genes involved in their signaling pathway—genes potentially involved in common forms of the disease, and an in vivo whole animal means to screen rapidly for novel therapeutics. Drug Dev Res 68:432–440, 2007. © 2008 Wiley‐Liss, Inc.

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The sodium pump and hypertension: A physiological role for the cardiac glycoside binding site of the Na,K-ATPase

Cited by 19 publications

References 27 publications

Antidiarrhoeal and antimicrobial activities of Emilia coccinea (Sims) G. Don extracts

Antidiarrhoeal and antimicrobial activities of Emilia coccinea (Sims) G. Don extracts

Regulation of sodium pump endocytosis by cardiotonic steroids: Molecular mechanisms and physiological implications

Monogenic migraine syndromes highlight novel drug targets

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