Regulation of the voltage-dependent sodium channel NaV1.1 by AKT1

Arribas-Blázquez, Marina; Piniella, Dolores; Olivos-Oré, Luis Alcides; Bartolomé-Martı́n, David; Leite, Cristiana; Giménez, Cecilio; Artalejo, Antonio R.; Zafra, Francisco

doi:10.1016/j.neuropharm.2021.108745

Cited by 10 publications

(11 citation statements)

References 67 publications

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“…[ 32 ] AKT1 is a serine/threonine kinase with paramount roles in many physiological and pathological processes, most notably in epileptogenesis. [ 33 ] CASP3 plays a key role in apoptosis following epileptic seizures and is integrally associated with neurodegeneration, neurogenesis, synaptogenesis, and astrocyte formation during the nascent phases of EP. [ 34 ] The absence of MAPK8 (JNK1) has been demonstrated to mitigate the onset and gravity of seizures while concurrently decreasing glial responsiveness, constraining pro-inflammatory gene expression, and impeding neuronal damage.…”

Section: Discussionmentioning

confidence: 99%

Understanding the molecular mechanisms of Acori Tatarinowii Rhizoma: Nardostahyos Radix et Rhizoma in epilepsy treatment using network pharmacology and molecular docking

Cheng,

Wang,

Wang

et al. 2024

Medicine

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Acori Tatarinowii Rhizoma (ATR) and Nardostahyos Radix et Rhizoma (NRR) are well-known traditional Chinese medicines that have been extensively used for the treatment of epilepsy (EP). However, the precise molecular mechanism of ATR-NRR action remains unclear because of their intricate ingredients. This study aimed to investigate the underlying mechanism of ATR-NRR in EP treatment using network pharmacology and molecular docking techniques. Herbal medicine and disease gene databases were searched to determine active constituents and shared targets of ATR-NRR and EP. A protein-protein interaction network was constructed using the STRING database, while the Gene Ontology and the Kyoto Encyclopedia of Genes and Genome pathway enrichment were performed using R programming. An ingredient-target-pathway network map was constructed using the Cytoscape software, incorporating network topology calculations to predict active ingredients and hub targets. The binding abilities of active ingredients and hub targets were examined using molecular docking. Nine qualified compounds and 53 common targets were obtained. The prominent active compounds were kaempferol, acacetin, cryptotanshinone, 8-isopentenyl-kaempferol, naringenin, and eudesmin, while the primary targets were RELA, AKT1, CASP3, MAPK8, JUN, TNF, and TP53. Molecular docking analysis revealed that they have substantial binding abilities. These 53 targets were found to influence EP by manipulating PI3K-Akt, IL-17, TNF, and apoptosis signaling pathways. The findings of this study indicate that ATR-NRR functions against EP by acting upon multiple pathways and targets, offering a basis for future study.

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Section: Discussionmentioning

confidence: 99%

Understanding the molecular mechanisms of Acori Tatarinowii Rhizoma: Nardostahyos Radix et Rhizoma in epilepsy treatment using network pharmacology and molecular docking

Cheng,

Wang,

Wang

et al. 2024

Medicine

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“…Recently, it was found that the activation of Akt can result in a robust decrease in the Na v 1.1-mediated sodium currents accompanied by significant changes in the inactivation of the channel. The effect of Akt was attributed to its ability to directly phosphorylate the Na v 1.1 channel [48]. Thus, the mechanism by which the pharmacological inhibition of Akt alters neuronal activity in our study could arise by directly preventing the kinase mediated phosphorylation of the Na v 1.6 channel, an indirect effect on the phosphorylation of the Na v 1.6 channel conferred by increasing the activity of GSK3, or a combination of these direct and indirect effects; however, future in vitro phosphorylation studies will be necessary to unequivocally address how the pharmacological inhibition of Akt alters the phosphorylation of the Na v 1.6 channel.…”

Section: Discussionmentioning

confidence: 99%

“…Posttranslational modifications such as phosphorylation play an essential role in regulating the function of Na v channels and have profound effects on the kinetics, subcellular localization, and trafficking of the channel, altering intrinsic the excitability and activity-dependent plasticity of the neurons [46]. Apart from a demonstration of a link between Akt and Na v 1.7 and Na v 1.8 in dorsal root ganglion (DRG) neurons [47] and demonstration of Akt importance in the regulation of Na v 1.1, which are critical for interneurons function [48], information on the relationship between Akt and Na v channels in the primary CNS neurons that are known to abundantly express the Na v 1.2 and Na v 1.6 channels is scarce. Providing evidence for a linkage between Akt and the Na v channel, we have previously elucidated a complex kinase network that involves a diverse array of proteins related to Akt that regulates the macromolecular complex of the Na v channel [49][50][51][52][53].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of the Akt/PKB Kinase Increases Nav1.6-Mediated Currents and Neuronal Excitability in CA1 Hippocampal Pyramidal Neurons

Marosi

Nenov

et al. 2022

IJMS

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In neurons, changes in Akt activity have been detected in response to the stimulation of transmembrane receptors. However, the mechanisms that lead to changes in neuronal function upon Akt inhibition are still poorly understood. In the present study, we interrogate how Akt inhibition could affect the activity of the neuronal Nav channels with while impacting intrinsic excitability. To that end, we employed voltage-clamp electrophysiological recordings in heterologous cells expressing the Nav1.6 channel isoform and in hippocampal CA1 pyramidal neurons in the presence of triciribine, an inhibitor of Akt. We showed that in both systems, Akt inhibition resulted in a potentiation of peak transient Na+ current (INa) density. Akt inhibition correspondingly led to an increase in the action potential firing of the CA1 pyramidal neurons that was accompanied by a decrease in the action potential current threshold. Complementary confocal analysis in the CA1 pyramidal neurons showed that the inhibition of Akt is associated with the lengthening of Nav1.6 fluorescent intensity along the axonal initial segment (AIS), providing a mechanism for augmented neuronal excitability. Taken together, these findings provide evidence that Akt-mediated signal transduction might affect neuronal excitability in a Nav1.6-dependent manner.

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“…The combination of excitatory or inhibitory transmitters with their corresponding receptors leads to ion channel activation, which plays an important role in epileptogenesis. Loss of function of NaV1.1 reduces electrical excitability of GABAergic neurons [ 49 ]; mutation of the α subunit of CaV2.1 suppresses neurotransmitter release mediated by the pre-synaptic neuronal membrane action potential [ 50 ]; and inactivation of KV1.2 leads to increased neurotransmitter release from excitatory neurons [ 51 ]. These ion channel changes affect the membrane potential and neurotransmitter release of neurons, ultimately triggering hypersynchronous firing and epileptogenesis.…”

Section: Molecular Mechanisms and Potential Drug Targets During Epile...mentioning

confidence: 99%

The Neurovascular Unit Dysfunction in the Molecular Mechanisms of Epileptogenesis and Targeted Therapy

Liu,

Zhang,

Zhao

et al. 2024

Neurosci. Bull.

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Epilepsy is a multifaceted neurological syndrome characterized by recurrent, spontaneous, and synchronous seizures. The pathogenesis of epilepsy, known as epileptogenesis, involves intricate changes in neurons, neuroglia, and endothelium, leading to structural and functional disorders within neurovascular units and culminating in the development of spontaneous epilepsy. Although current research on epilepsy treatments primarily centers around anti-seizure drugs, it is imperative to seek effective interventions capable of disrupting epileptogenesis. To this end, a comprehensive exploration of the changes and the molecular mechanisms underlying epileptogenesis holds the promise of identifying vital biomarkers for accurate diagnosis and potential therapeutic targets. Emphasizing early diagnosis and timely intervention is paramount, as it stands to significantly improve patient prognosis and alleviate the socioeconomic burden. In this review, we highlight the changes and molecular mechanisms of the neurovascular unit in epileptogenesis and provide a theoretical basis for identifying biomarkers and drug targets.

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Regulation of the voltage-dependent sodium channel NaV1.1 by AKT1

Cited by 10 publications

References 67 publications

Understanding the molecular mechanisms of Acori Tatarinowii Rhizoma: Nardostahyos Radix et Rhizoma in epilepsy treatment using network pharmacology and molecular docking

Understanding the molecular mechanisms of Acori Tatarinowii Rhizoma: Nardostahyos Radix et Rhizoma in epilepsy treatment using network pharmacology and molecular docking

Inhibition of the Akt/PKB Kinase Increases Nav1.6-Mediated Currents and Neuronal Excitability in CA1 Hippocampal Pyramidal Neurons

The Neurovascular Unit Dysfunction in the Molecular Mechanisms of Epileptogenesis and Targeted Therapy

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