Ouabain induces endocytosis and degradation of tight junction proteins through ERK1/2-dependent pathways

Rincón-Heredia, Ruth; Flores-Benítez, David; Flores-Maldonado, Catalina; Bonilla-Delgado, José; García-Hernández, Vicky; Verdejo-Torres, Odette; Castillo, Aida; Larre, Isabel; Poot-Hernández, Augusto César; Franco, Martha; Gariglio, Patricio; Reyes, José L.; Contreras, Rubén G.

doi:10.1016/j.yexcr.2013.10.008

Cited by 30 publications

(31 citation statements)

References 63 publications

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“…In recent studies, we found that 10 nM ouabain provokes a single wave of c-Src and ERK1/2 phosphorylation that peaks within the first hour of application, coinciding with the peak of GJC. Furthermore, incubation in PP2 inhibits c-Src, and incubation in PD98059 inhibits MEK kinase at least for 8 h [12]. These signaling proteins also modulate the effect of ouabain on TJ [14] and ciliogenesis [15].…”

Section: Resultsmentioning

confidence: 99%

“…High levels of ouabain (≥ 300 nM) activate the retrieval of cell-adhesion molecules that are associated with, or form part of the plasma membrane, and this process causes the cells to detach (e.g., MDCK cells) from the substrate as well as from one another [11,12]. Therefore, we hypothesized that one physiological role of ouabain is the modulation of cell contacts [9,13].…”

Section: Introductionmentioning

confidence: 99%

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Ouabain Increases Gap Junctional Communication in Epithelial Cells

Ponce

Larre

Castillo

et al. 2014

Cell Physiol Biochem

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Background/Aims: The finding that endogenous ouabain acts as a hormone prompted efforts to elucidate its physiological function. In previous studies, we have shown that 10 nM ouabain (i.e., a concentration within the physiological range) modulates cell-cell contacts such as tight junctions and apical/basolateral polarity. In this study, we examined whether 10 nM ouabain affects another important cell-cell feature: gap junction communication (GJC). Methods: We employed two different approaches: 1) analysis of the cell-to-cell diffusion of neurobiotin injected into a particular MDCK cell (epithelial cells from dog kidneys) in a confluent monolayer by counting the number of neighboring cells reached by the probe and 2) measurement of the electrical capacitance. Results: We found that 10 nM ouabain increase GJC by 475% within 1 hour. The Na+-K+-ATPase acts as a receptor of ouabain. In previous works we have shown that ouabain activates c-Src and ERK1/2 in 1 hour; in the present study we show that the inhibition of these proteins block the effect of ouabain on GJC. This increase in GJC does not require synthesis of new protein components, because the inhibitors cycloheximide and actinomycin D did not affect this phenomenon. Using silencing assays we also demonstrate that this ouabain-induced enhancement of GJC involves connexins 32 and 43. Conclusion: Ouabain 10 nM increases GJC in MDCK cells.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Ouabain Increases Gap Junctional Communication in Epithelial Cells

Ponce

Larre

Castillo

et al. 2014

Cell Physiol Biochem

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“…RhoA and Rho‐associated kinase (ROCK) are key regulators of IFN‐γ–induced endocytosis of epithelial TJ proteins and JAM‐A macropinocytosis, while c‐JNK regulates caveolae‐ and clathrin‐dependent endocytosis and macropinocytosis of occludin . The MAP kinase ERK1/2 modulates internalization and degradation of TJ proteins claudin‐2, claudin‐4, occludin, and ZO‐1 . In TJ endocytic sorting, a recent study showed a close association between ZO‐2 and SNX27 in an epithelial mpkCCD cell line, suggesting a role in endocytic pathways …”

Section: Signaling Pathways In Endocytic Sorting Of Tj Proteinsmentioning

confidence: 99%

Endocytosis of tight junction proteins and the regulation of degradation and recycling

Stamatovic¹,

Johnson²,

Sladojević

et al. 2017

Annals of the New York Academy of Sciences

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Internalization of tight junction (TJ) proteins from the plasma membrane is a pivotal mechanism regulating TJ plasticity and function in both epithelial and endothelial barrier tissues. Once internalized, the TJ proteins enter complex vesicular machinery, where further trafficking is directly dependent on the initiating stimulus and downstream signaling pathways that regulate the sorting and destiny of TJ proteins, as well as on cell and barrier responses. The destiny of internalized TJ proteins is recycling to the plasma membrane or sorting to late endosomes and degradation. This review highlights recent advances in our knowledge of endocytosis and vesicular trafficking of TJ proteins in both epithelial and endothelial cells. A greater understanding of these processes may allow for the development of methods to modulate barrier permeability for drug delivery or preventing barrier dysfunction in disease states.

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“…The laboratory of Zijian Xie made an important discovery by demonstrating that a population of non-ion-transporting and highaffinity Na C /K C ATPase resides in caveolae, forming a signaling complex with Src kinase (Pierre & Xie 2006). When cardiotonic steroids at low picomolar to nanomolar concentrations bind to Na C /K C ATPase in the caveolae, this activates Src, which in turn results in transactivation of EGFR and activation of the PI3K-Akt pathway, the Ras-Raf-ERK MAP kinase pathway, IP3R activation, and calcium oscillations, resulting in regulation of earlyresponse genes associated with cell growth, motility, and metabolic pathways (Peng et al 1996, Kometiani et al 1998, Contreras et al 1999, Aizman et al 2001, Abramowitz et al 2003, Dmitrieva & Doris 2003, Dong et al 2004, Khundmiri et al 2006, Liu & Askari 2006, Liu et al 2007a,b, 2011, Pierre et al 2008, Quintas et al 2010, Morrill et al 2012, Bai et al 2013, Wu et al 2013, Rincon-Heredia et al 2014.…”

Section: Namentioning

confidence: 99%

Advances in understanding the role of cardiac glycosides in control of sodium transport in renal tubules

Khundmiri¹

2014

Journal of Endocrinology

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Cardiotonic steroids have been used for the past 200 years in the treatment of congestive heart failure. As specific inhibitors of membrane-bound Na C /K C ATPase, they enhance cardiac contractility through increasing myocardial cell calcium concentration in response to the resulting increase in intracellular Na concentration. The half-minimal concentrations of cardiotonic steroids required to inhibit Na C /K C ATPase range from nanomolar to micromolar concentrations. In contrast, the circulating levels of cardiotonic steroids under physiological conditions are in the low picomolar concentration range in healthy subjects, increasing to high picomolar levels under pathophysiological conditions including chronic kidney disease and heart failure. Little is known about the physiological function of low picomolar concentrations of cardiotonic steroids. Recent studies have indicated that physiological concentrations of cardiotonic steroids acutely stimulate the activity of Na C /K C ATPase and activate an intracellular signaling pathway that regulates a variety of intracellular functions including cell growth and hypertrophy. The effects of circulating cardiotonic steroids on renal salt handling and total body sodium homeostasis are unknown. This review will focus on the role of low picomolar concentrations of cardiotonic steroids in renal Na C /K C ATPase activity, cell signaling, and blood pressure regulation.

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Ouabain induces endocytosis and degradation of tight junction proteins through ERK1/2-dependent pathways

Cited by 30 publications

References 63 publications

Ouabain Increases Gap Junctional Communication in Epithelial Cells

Ouabain Increases Gap Junctional Communication in Epithelial Cells

Endocytosis of tight junction proteins and the regulation of degradation and recycling

Advances in understanding the role of cardiac glycosides in control of sodium transport in renal tubules

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