Rapid Na+ accumulation by a sustained action potential impairs mitochondria function and induces apoptosis in HEK293 cells expressing non-inactivating Na+ channels

Kawasaki, Koichiro; Imaizumi, Yuji; Yamamura, Hisao; Imaizumi, Yuji

doi:10.1016/j.bbrc.2019.03.129

Cited by 5 publications

(5 citation statements)

References 20 publications

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“…The fact that SCN1A variants generally cause less severe developmental phenotypes is possibly related to its later upregulation after birth. In addition to defective brain maturation, which is continuing during infancy and childhood, neural network-independent mechanisms, like direct cytotoxicity due for example to Na + overloading could play an additional role [ 84 ].…”

Section: Vgsc In Intellectual Disabilitymentioning

confidence: 99%

Voltage-Gated Sodium Channel Dysfunctions in Neurological Disorders

Barbieri

Nizzari

Zanardi

et al. 2023

Life

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The pore-forming subunits (α subunits) of voltage-gated sodium channels (VGSC) are encoded in humans by a family of nine highly conserved genes. Among them, SCN1A, SCN2A, SCN3A, and SCN8A are primarily expressed in the central nervous system. The encoded proteins Nav1.1, Nav1.2, Nav1.3, and Nav1.6, respectively, are important players in the initiation and propagation of action potentials and in turn of the neural network activity. In the context of neurological diseases, mutations in the genes encoding Nav1.1, 1.2, 1.3 and 1.6 are responsible for many forms of genetic epilepsy and for Nav1.1 also of hemiplegic migraine. Several pharmacological therapeutic approaches targeting these channels are used or are under study. Mutations of genes encoding VGSCs are also involved in autism and in different types of even severe intellectual disability (ID). It is conceivable that in these conditions their dysfunction could indirectly cause a certain level of neurodegenerative processes; however, so far, these mechanisms have not been deeply investigated. Conversely, VGSCs seem to have a modulatory role in the most common neurodegenerative diseases such as Alzheimer’s, where SCN8A expression has been shown to be negatively correlated with disease severity.

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Section: Vgsc In Intellectual Disabilitymentioning

confidence: 99%

Voltage-Gated Sodium Channel Dysfunctions in Neurological Disorders

Barbieri

Nizzari

Zanardi

et al. 2023

Life

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“…In a model resembling epilepsy, hippocampal neurons from rats injected with kainic acid (an NMDA type glutamate receptor agonist) underwent apoptosis that was attenuated upon inclusion of various voltagegated sodium channel blockers (Das et al, 2010). An increase in intracellular sodium following abnormal hyperexcitation can result in death of neurons, and a recent study probing the mechanism of this model suggested this death occurs via sodium accumulation and/or concomitant potassium loss that impairs mitochondrial function (Kawasaki et al, 2019). Genistein, a primary isoflavone found in soybeans, was shown to inhibit cell death in an in vitro model of primary neurons under hypoxicischemia (oxygen-glucose deprivation) conditions in part by reversing the classic increase in potassium efflux and decreasing the sodium influx (Ma et al, 2016).…”

Section: Neuronal Cells and Cell Deathmentioning

confidence: 99%

Ions, the Movement of Water and the Apoptotic Volume Decrease

Bortner

Cidlowski

2020

Front. Cell Dev. Biol.

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The movement of water across the cell membrane is a natural biological process that occurs during growth, cell division, and cell death. Many cells are known to regulate changes in their cell volume through inherent compensatory regulatory mechanisms. Cells can sense an increase or decrease in their cell volume, and compensate through mechanisms known as a regulatory volume increase (RVI) or decrease (RVD) response, respectively. The transport of sodium, potassium along with other ions and osmolytes allows the movement of water in and out of the cell. These compensatory volume regulatory mechanisms maintain a cell at near constant volume. A hallmark of the physiological cell death process known as apoptosis is the loss of cell volume or cell shrinkage. This loss of cell volume is in stark contrast to what occurs during the accidental cell death process known as necrosis. During necrosis, cells swell or gain water, eventually resulting in cell lysis. Thus, whether a cell gains or loses water after injury is a defining feature of the specific mode of cell death. Cell shrinkage or the loss of cell volume during apoptosis has been termed apoptotic volume decrease or AVD. Over the years, this distinguishing feature of apoptosis has been largely ignored and thought to be a passive occurrence or simply a consequence of the cell death process. However, studies on AVD have defined an underlying movement of ions that result in not only the loss of cell volume, but also the activation and execution of the apoptotic process. This review explores the role ions play in controlling not only the movement of water, but the regulation of apoptosis. We will focus on what is known about specific ion channels and transporters identified to be involved in AVD, and how the movement of ions and water change the intracellular environment leading to stages of cell shrinkage and associated apoptotic characteristics. Finally, we will discuss these concepts as they apply to different cell types such as neurons, cardiomyocytes, and corneal epithelial cells.

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“…Therefore, ATP synthase determines the path along which the ischemic destruction of neurons will proceed: its high initial level suggests shrinkage of neurons, and its low initial level implies transformation into shadow cells. Shrinkage of neurons in this case is explained by the accumulation of intracellular Na+ due to dysfunction of the energydependent Na+ pump during ischemia [19][20][21], which inevitably leads to irreversible damage to mitochondria [23,24] and can be expressed in a change in the shape of perikaryons, chromatophilia of neuronal cytoplasm, opening of pathological mitochondrial pores and further lead to cell death [24]. The revealed negative correlations between the amount of Ngb and shadow cells demonstrate the protective effect of Ngb during short-term ischemic exposure, especially in the brainstem and cerebellum.…”

Section: Discussionmentioning

confidence: 99%

"ATP Synthase and Neuroglobin as Factors Determining the Path of Neuronal Destruction in Cerebral Ischemia"

Bon¹

2022

BJSTR

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Rapid Na+ accumulation by a sustained action potential impairs mitochondria function and induces apoptosis in HEK293 cells expressing non-inactivating Na+ channels

Cited by 5 publications

References 20 publications

Voltage-Gated Sodium Channel Dysfunctions in Neurological Disorders

Voltage-Gated Sodium Channel Dysfunctions in Neurological Disorders

Ions, the Movement of Water and the Apoptotic Volume Decrease

"ATP Synthase and Neuroglobin as Factors Determining the Path of Neuronal Destruction in Cerebral Ischemia"

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Rapid Na+ accumulation by a sustained action potential impairs mitochondria function and induces apoptosis in HEK293 cells expressing non-inactivating Na+ channels

Cited by 5 publications

References 20 publications

Voltage-Gated Sodium Channel Dysfunctions in Neurological Disorders

Voltage-Gated Sodium Channel Dysfunctions in Neurological Disorders

Ions, the Movement of Water and the Apoptotic Volume Decrease

"ATP Synthase and Neuroglobin as Factors Determining the Path of Neuronal Destruction in Cerebral Ischemia"

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Rapid Na+ accumulation by a sustained action potential impairs mitochondria function and induces apoptosis in HEK293 cells expressing non-inactivating Na+ channels