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Cited by 30Ion channel regulation and functionEpilepsy research and treatmentNeuroscience and Neuropharmacology Research

The neuronal serum- and glucocorticoid-regulated kinase 1.1 reduces neuronal excitability and protects against seizures through upregulation of the M-current

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Miranda, Pablo, Cadaveira-Mosquera, Alba, González-Montelongo, Rafaela, Villarroel, Alvaro, González-Hernández, Tomás, Lamas, J. Antonio, Alvarez de la Rosa, Diego, Giraldez, Teresa·2013·The Journal of Neuroscience
DOI 10.1523/jneurosci.3442-12.2013PMC PMC6619182
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Abstract

The M-current formed by tetramerization of Kv7.2 and Kv7.3 subunits is a neuronal voltage-gated K+conductance that controls resting membrane potential and cell excitability. In Xenopus laevis oocytes, an increase in Kv7.2/3 function by the serum- and glucocorticoid-regulated kinase 1 (SGK1) has been reported previously (Schuetz et al., 2008). We now show that the neuronal isoform of this kinase (SGK1.1), with distinct subcellular localization and modulation, upregulates the Kv7.2/3 current in Xenopus oocytes and mammalian human embryonic kidney HEK293 cells. In contrast to the ubiquitously expressed SGK1, the neuronal isoform SGK1.1 interacts with phosphoinositide-phosphatidylinositol 4,5-bisphosphate (PIP 2) and is distinctly localized to the plasma membrane (Arteaga et al., 2008). An SGK1.1 mutant with disrupted PIP 2 binding sites produced no effect on Kv7.2/3 current amplitude. SGK1.1 failed to modify the voltage dependence of activation and did not change activation or deactivation kinetics of Kv7.2/3 channels. These results suggest that the kinase increases channel membrane abundance, which was confirmed with flow cytometry assays. To evaluate the effect of the kinase in neuronal excitability, we generated a transgenic mouse (Tg.sgk) expressing a constitutively active form of SGK1.1 (S515D). Superior cervical ganglion (SCG) neurons isolated from Tg.sgk mice showed a significant increase in M-current levels, paralleled by reduced excitability and more negative resting potentials. SGK1.1 effect on M-current in Tg.sgk–SCG neurons was counteracted by muscarinic receptor activation. Transgenic mice with increased SGK1.1 activity also showed diminished sensitivity to kainic acid-induced seizures. Altogether, our results unveil a novel role of SGK1.1 as a physiological regulator of the M-current and neuronal excitability.

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Authors
Miranda, P., Cadaveira-Mosquera, A., González-Montelongo, R., Villarroel, A., González-Hernández, T., Lamas, J. A., Alvarez de la Rosa, D., & Giraldez, T.
Affiliations
  • Hospital Universitario Nuestra Señora de Candelaria (ES)
  • Universidade de Vigo (ES)
ORCID
Venue
The Journal of Neuroscience
Publisher
Society for Neuroscience
Published
2013-02-06
Volume
33
Issue
6
Pages
2684-2696
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
DOI
10.1523/jneurosci.3442-12.2013
PMC
PMC6619182
OpenAlex
W2170493982
Cited by
30
References
1
Citations by year
2026: 3 · 2025: 2 · 2024: 4 · 2023: 1 · 2022: 1 · 2021: 6 · 2020: 1 · 2019: 2 · 2018: 1 · 2017: 1 · 2015: 1 · 2014: 3 · 2013: 4
FWCI
1.20
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • European Commission
  • Ministerio de Ciencia e Innovación
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
  • Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
M-current, neuronal excitability, PIP2 binding, resting membrane potential, superior cervical ganglion neurons, kainic acid-induced seizures, muscarinic receptors, transgenic mouse model, seizure protection
MeSH terms
Serum-Glucocorticoid Regulated Kinases, Animals, Cells, Cultured, Female, Humans, Membrane Potentials, Mice, Inbred C57BL, Mice, Transgenic, Neurons, Seizures, Xenopus laevis, Up-Regulation, Protein Serine-Threonine Kinases, Immediate-Early Proteins, Mice, KCNQ2 Potassium Channel, KCNQ3 Potassium Channel, HEK293 Cells

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