Ouabain Enhances Gap Junctional Intercellular Communication by Inducing Paracrine Secretion of Prostaglandin E2

Toro, Alejandro Ogazon del; Jimenez, Lidia; Rubi, Mauricio Serrano; Cereijido, Marcelino; Ponce, Arturo

doi:10.3390/ijms22126244

Cited by 3 publications

(1 citation statement)

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“…Low concentrations of ouabain promote intercellular junction formation and intercellular signaling, but higher concentrations uncouple cells ( 8 , 12 , 515 ). A good example is the action of ouabain on Madin-Darby canine kidney (MDCK) cells described by Cereijido and Ponce ( 515 , 516 ). Ouabain (10 nM) enhances the formation of “tight” “gap junctions” and, thus, intercellular communication, by increasing E-cadherin and β-catenin expression in the PM.…”

Section: The Physiology and Pathophysiology Of Cts-nka Interactionsmentioning

confidence: 99%

Sensational site: the sodium pump ouabain-binding site and its ligands

Blaustein,

Hamlyn

2024

American Journal of Physiology-Cell Physiology

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Cardiotonic steroids (CTS), used by certain insects, toads, and rats for protection from predators, became, thanks to Withering's trailblazing 1785 monograph, the mainstay of heart failure (HF) therapy. In the 1950's and 60's we learned that the CTS receptor was part of the sodium pump (NKA) and that the Na+/Ca2+ exchanger was critical for the acute cardiotonic effect of digoxin- and ouabain-related CTS. This "settled" view was upended by seven revolutionary observations. First, sub-nanomolar ouabain sometimes stimulates NKA whilst higher concentrations are invariably inhibitory. Second, endogenous ouabain (EO) was discovered in the human circulation. Third, in the DIG clinical trial, digoxin only marginally improved outcome in HF patients. Fourth, cloning of NKA in 1985 revealed multiple NKA α and β subunit isoforms that, in the rodent, differ in their sensitivities to CTS. Fifth, the NKA is a cation pump and a hormone receptor/signal transducer. EO binding to NKA activates, in a ligand- and cell-specific manner, several protein kinase and Ca2+-dependent signaling cascades that have widespread physiological effects and can contribute to hypertension and HF pathogenesis. Sixth, all CTS are not equivalent: e.g., ouabain induces hypertension in rodents while digoxin is anti-hypertensinogenic ("biased signaling"). Seventh, most common rodent hypertension models require a highly ouabain-sensitive α2 NKA and the elevated blood pressure is alleviated by EO immunoneutralization. These numerous activities are enabled by NKA's intricate structure. We have just begun to understand the endocrine role of the endogenous ligands and the broad impact of the ouabain binding site on physiology and pathophysiology.

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Section: The Physiology and Pathophysiology Of Cts-nka Interactionsmentioning

confidence: 99%

Sensational site: the sodium pump ouabain-binding site and its ligands

Blaustein,

Hamlyn

2024

American Journal of Physiology-Cell Physiology

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Endogenous Cardiac Steroids in Bipolar Disorder: State of the Art

El‐Mallakh

Sampath²,

Horesh³

et al. 2022

IJMS

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Bipolar disorder (BD) is a severe psychiatric illness with a poor prognosis and problematic, suboptimal, treatments. Treatments, borne of an understanding of the pathoetiologic mechanisms, need to be developed in order to improve outcomes. Dysregulation of cationic homeostasis is the most reproducible aspect of BD pathophysiology. Correction of ionic balance is the universal mechanism of action of all mood stabilizing medications. Endogenous sodium pump modulators (collectively known as endogenous cardiac steroids, ECS) are steroids which are synthesized in and released from the adrenal gland and brain. These compounds, by activating or inhibiting Na+, K+-ATPase activity and activating intracellular signaling cascades, have numerous effects on cell survival, vascular tone homeostasis, inflammation, and neuronal activity. For the past twenty years we have addressed the hypothesis that the Na+, K+-ATPase-ECS system may be involved in the etiology of BD. This is a focused review that presents a comprehensive model pertaining to the role of ECS in the etiology of BD. We propose that alterations in ECS metabolism in the brain cause numerous biochemical changes that underlie brain dysfunction and mood symptoms. This is based on both animal models and translational human results. There are data that demonstrate that excess ECS induce abnormal mood and activity in animals, while a specific removal of ECS with antibodies normalizes mood. There are also data indicating that circulating levels of ECS are lower in manic individuals, and that patients with BD are unable to upregulate synthesis of ECS under conditions that increase their elaboration in non-psychiatric controls. There is strong evidence for the involvement of ion dysregulation and ECS function in bipolar illness. Additional research is required to fully characterize these abnormalities and define future clinical directions.

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Influence of Cardiac Glycosides and Prostaglandins on the Physiology of Epithelial Cells

Ponce¹,

Shoshani²,

Toro³

et al. 2023

Human Physiology - Annual Volume 2023 [Working Title]

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Epithelial cells play a major role in animal and human homeostasis because they selectively regulate the exchange of solutes between two given media, such as blood or urine. Cardiac glycosides (CG) are a group of highly toxic compounds whose best therapeutic known effect is on heart, although recent evidence has shown that it exerts a wide range of physiological effects on cells and tissues other than the heart. Prostaglandins, on the other hand, are a group of lipids that produce diverse physiological and pathological effects among which inflammation stands out. In this chapter, we describe that cardiac glycosides modulate key features of epithelial cell physiology, including cell-cell contact junctional complexes, cilliogenesis, and gap junction-mediated intercellular communication (GJIC) in epithelial cells. Prostaglandin PGE2 also modulates GJIC through a different signaling pathway. In addition, we describe that CG induce paracrine release of prostaglandin PGE2, which in turn modulates GJIC by itself.

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Ouabain Enhances Gap Junctional Intercellular Communication by Inducing Paracrine Secretion of Prostaglandin E2

Cited by 3 publications

References 79 publications

Sensational site: the sodium pump ouabain-binding site and its ligands

Sensational site: the sodium pump ouabain-binding site and its ligands

Endogenous Cardiac Steroids in Bipolar Disorder: State of the Art

Influence of Cardiac Glycosides and Prostaglandins on the Physiology of Epithelial Cells

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