The vascular Na,K-ATPase: clinical implications in stroke, migraine, and hypertension

Staehr, Christian; Aalkjaer, Christian; Matchkov, Vladimir V.

doi:10.1042/cs20220796

Cited by 7 publications

(4 citation statements)

References 264 publications

(446 reference statements)

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“…Notably, cancer emerges as a significant focus, with numerous studies underscoring the impact of the GC–NKA interaction on various aspects of cancer progression, such as proliferation [ 182 ], adhesion [ 267 ], intercellular communication via gap junctions [ 268 ], epithelial–mesenchymal transition, and apoptosis [ 269 ]. Additionally, other disorders unrelated to cancer but of considerable interest, such as obesity [ 222 ], hypertension [ 270 ], and metabolic disorders [ 271 ], as well as neurological conditions like epilepsy and Alzheimer’s disease [ 187 , 272 ], have been implicated.…”

Section: Discussion and Perspectivementioning

confidence: 99%

Na+/K+-ATPase: More than an Electrogenic Pump

Contreras,

Torres-Carrillo,

Flores-Maldonado

et al. 2024

IJMS

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The sodium pump, or Na+/K+-ATPase (NKA), is an essential enzyme found in the plasma membrane of all animal cells. Its primary role is to transport sodium (Na+) and potassium (K+) ions across the cell membrane, using energy from ATP hydrolysis. This transport creates and maintains an electrochemical gradient, which is crucial for various cellular processes, including cell volume regulation, electrical excitability, and secondary active transport. Although the role of NKA as a pump was discovered and demonstrated several decades ago, it remains the subject of intense research. Current studies aim to delve deeper into several aspects of this molecular entity, such as describing its structure and mode of operation in atomic detail, understanding its molecular and functional diversity, and examining the consequences of its malfunction due to structural alterations. Additionally, researchers are investigating the effects of various substances that amplify or decrease its pumping activity. Beyond its role as a pump, growing evidence indicates that in various cell types, NKA also functions as a receptor for cardiac glycosides like ouabain. This receptor activity triggers the activation of various signaling pathways, producing significant morphological and physiological effects. In this report, we present the results of a comprehensive review of the most outstanding studies of the past five years. We highlight the progress made regarding this new concept of NKA and the various cardiac glycosides that influence it. Furthermore, we emphasize NKA’s role in epithelial physiology, particularly its function as a receptor for cardiac glycosides that trigger intracellular signals regulating cell–cell contacts, proliferation, differentiation, and adhesion. We also analyze the role of NKA β-subunits as cell adhesion molecules in glia and epithelial cells.

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Section: Discussion and Perspectivementioning

confidence: 99%

Na+/K+-ATPase: More than an Electrogenic Pump

Contreras,

Torres-Carrillo,

Flores-Maldonado

et al. 2024

IJMS

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“…A channelopathy may cause an abnormal “gain of function” (such as myokymia ( 101 ) and ptosis ( 102 ), that are commonly missed by practitioners, even though they are often associated with migraine), or an abnormal loss of function (such as weakness or numbness) depending on whether loss of channel function leads to excessive excitability or to lack of excitability ( 103 ). In the case of migraine, several ionic channels are genetic variants, including the sodium-potassium ATPase (Na + /K + /ATPase) channel, which is responsible for resetting the membrane potential to resting state ( 104 ) to rebuild the saltatory conduction. In addition, visiting the human genome database ( 105 ) and looking at the currently discovered genetic variants associated with migraine, in order of relevance of the variant to migraine, the first three most relevant variants out of 3,866 to date are the ATP1A2 (Na + /K + /ATPase Subunit Alpha 2), CACNA1A (Calcium Voltage-Gated Channel Subunit Alpha A), and SCN1A (Sodium Voltage-Gated Channel Alpha Subunit 1).…”

Section: The Cause Of Migrainementioning

confidence: 99%

Specifically formulated ketogenic, low carbohydrate, and carnivore diets can prevent migraine: a perspective

Stanton

2024

Front. Nutr.

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This article presents a hypothesis explaining the cause of migraines, suggesting that electrolyte imbalance, specifically a lack of sufficient sodium in the extracellular space of sensory neurons, leads to failed action potentials. The author argues that migraines are triggered when sodium channels fail to initiate action potentials, preventing communication between neurons. The article discusses the evolutionary perspective of the migraine brain, stating that migraineurs have a hypersensitive brain with more sensory neuronal connections, making them more reactive to environmental stimuli and in need of more minerals for the increased sensory neuronal communication. Since glucose is often used to reduce serum hypernatremia, it follows that a high carbohydrate diet reduces sodium availability for use in the brain, causing an electrolyte imbalance. Low carbohydrate diets, such as ketogenic, low carb-high fat (LCHF), and carnivore (all animal products), can be beneficial for migraineurs by reducing/eliminating carbohydrate intake, thereby increasing sodium availability. In support, many research papers and some anecdotal evidences are referred to. The article concludes by proposing lifestyle modifications, such as dietary changes and sodium intake management. These will provide migraineurs with a long-term healthy metabolic foundation helping them to maintain strong nutritional adherence and with that aiding continued proper neuronal functioning and migraine free life.

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“…As emphasized in a recent review ( 588 ), in addition to helping regulate intracellular Ca 2+ by influencing the Na + gradient and NCX, EO also helps regulate the Ca 2+ sensitivity of the VSM contractile apparatus. It does so by promoting the phosphorylation of cSrc which, in turn, promotes the phosphorylation of myosin phosphatase target subunit 1 (MYPT1); this inhibits myosin light-chain phosphatase ( 589 ).…”

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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The vascular Na,K-ATPase: clinical implications in stroke, migraine, and hypertension

Cited by 7 publications

References 264 publications

Na+/K+-ATPase: More than an Electrogenic Pump

Na+/K+-ATPase: More than an Electrogenic Pump

Specifically formulated ketogenic, low carbohydrate, and carnivore diets can prevent migraine: a perspective

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

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