SGK1.1 limits brain damage after status epilepticus through M current-dependent and independent mechanisms

Martín-Batista, Elva; Maglio, Laura E.; Armas-Capote, Natalia; Hernández, Guadalberto; Rosa, Diego Álvarez de la; Giráldez, Teresa

doi:10.1016/j.nbd.2021.105317

Cited by 4 publications

(4 citation statements)

References 57 publications

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“…In fact, some studies demonstrating activation of Kv7.3/5 by retigabine suggested it might constitute a molecular target for this agent along with Kv7.2/3 (Wickenden et al, 2001). In addition, SGK1.1 is mainly expressed in pyramidal neurons (Wesch et al, 2010;Martin-Batista et al, 2021). Altogether, these data indicate that SGK1.1 activation could be a promising therapeutic target for epilepsy, as it shares the mechanism of action of retigabine without substantial risk of activating potassium channels expressed outside neuronal tissue.…”

Section: Discussionmentioning

confidence: 92%

“…For SGK1.1 detection we used a rabbit polyclonal antibody produced in our laboratory (Martin-Batista et al, 2021). SGK1 was detected using rabbit anti-SGK1 polyclonal antibody (Abcam, ab43606).…”

Section: Antibodiesmentioning

confidence: 99%

“…We previously described that SGK1.1, the neuronal isoform of the serum and glucocorticoid-induced kinase 1 (SGK1), increases membrane abundance of Kv7.2/3 channels in a PIP 2 -dependent manner, resulting in augmented current levels and providing a convergence point to M-channel regulation (Miranda et al, 2013). Recently, we described that augmentation of M-channel activity by transgenic co-expression of constitutively active SGK1.1 potently reduces seizure severity and duration in a kainic acid mouse model of temporal lobe epilepsy (Armas-Capote et al, 2020) and contributes to neuroprotection (Martin-Batista et al, 2021). However, the wider effects of SGK1.1 on the Kv7 family of channels forming the neuronal M-current have not been directly addressed and, most importantly, its potential role in rescuing epileptogenic mutations such as those found in Kv7.2 (R207W and A306T) is currently unknown.…”

Section: Introductionmentioning

confidence: 99%

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Activation of SGK1.1 Upregulates the M-current in the Presence of Epilepsy Mutations

Martín-Batista

Manville

Rivero-Pérez

et al. 2021

Front. Mol. Neurosci.

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In the central nervous system, the M-current plays a critical role in regulating subthreshold electrical excitability of neurons, determining their firing properties and responsiveness to synaptic input. The M-channel is mainly formed by subunits Kv7.2 and Kv7.3 that co-assemble to form a heterotetrametric channel. Mutations in Kv7.2 and Kv7.3 are associated with hyperexcitability phenotypes including benign familial neonatal epilepsy (BFNE) and neonatal epileptic encephalopathy (NEE). SGK1.1, the neuronal isoform of the serum and glucocorticoids-regulated kinase 1 (SGK1), increases M-current density in neurons, leading to reduced excitability and protection against seizures. Herein, using two-electrode voltage clamp on Xenopus laevis oocytes, we demonstrate that SGK1.1 selectively activates heteromeric Kv7 subunit combinations underlying the M-current. Importantly, activated SGK1.1 increases M-channel activity in the presence of two different epilepsy mutations found in Kv7.2, R207W and A306T. In addition, proximity ligation assays in the N2a cell line allowed us to address the effect of these mutations on Kv7-SGK1.1-Nedd4 molecular associations, a proposed pathway underlying augmentation of M-channel activity by SGK1.1

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Section: Discussionmentioning

confidence: 92%

Section: Antibodiesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Activation of SGK1.1 Upregulates the M-current in the Presence of Epilepsy Mutations

Martín-Batista

Manville

Rivero-Pérez

et al. 2021

Front. Mol. Neurosci.

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“…NeuroD2, Mc1r, Timp3 and Nfkbia were all upregulated at 5 weeks after treatment, and were associated with protection against neuroinflammation, promotion of cell survival, and attenuation of neuronal and cognitive damage in numerous animal models ( Fridmacher et al, 2003 ; Gibb et al, 2015 ; Fu et al, 2020 ; Pang and Shi, 2021 ; Xu et al, 2021 ). Among these upregulated genes, Sgk1 in particular was associated with cell survival in the aging brain ( Sahin et al, 2013 ), and highly protective against a broad range of neurotoxins ( Iqbal et al, 2015 ) and pathologies ( Lee et al, 2020 ; Martin-Batista et al, 2021 ).…”

Section: Resultsmentioning

confidence: 99%

Hippocampal differential expression underlying the neuroprotective effect of delta-9-tetrahydrocannabinol microdose on old mice

et al. 2023

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Delta-9-tetrahydrocannabinol (THC) is the primary psychoactive compound of the cannabis plant and an exogenous ligand of the endocannabinoid system. In previous studies, we demonstrated that a single microdose of THC (0.002 mg/kg, 3–4 orders of magnitude lower than the standard dose for rodents) exerts distinct, long-term neuroprotection in model mice subjected to acute neurological insults. When administered to old, healthy mice, the THC microdose induced remarkable long-lasting (weeks) improvement in a wide range of cognitive functions, including significant morphological and biochemical brain alterations. To elucidate the mechanisms underlying these effects, we analyzed the gene expression of hippocampal samples from the model mice. Samples taken 5 days after THC treatment showed significant differential expression of genes associated with neurogenesis and brain development. In samples taken 5 weeks after treatment, the transcriptional signature was shifted to that of neuronal differentiation and survival. This study demonstrated the use of hippocampal transcriptome profiling in uncovering the molecular basis of the atypical, anti-aging effects of THC microdose treatment in old mice.

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SGK1.1 isoform is involved in nociceptive modulation, offering a protective effect against noxious cold stimulus in a sexually dimorphic manner

Mercado

Paniagua

Sánchez-Robles

et al. 2022

Pharmacology Biochemistry and Behavior

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SGK1.1 limits brain damage after status epilepticus through M current-dependent and independent mechanisms

Cited by 4 publications

References 57 publications

Activation of SGK1.1 Upregulates the M-current in the Presence of Epilepsy Mutations

Activation of SGK1.1 Upregulates the M-current in the Presence of Epilepsy Mutations

Hippocampal differential expression underlying the neuroprotective effect of delta-9-tetrahydrocannabinol microdose on old mice

SGK1.1 isoform is involved in nociceptive modulation, offering a protective effect against noxious cold stimulus in a sexually dimorphic manner

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