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- Title
The Neuronal Serum- and Glucocorticoid-Regulated Kinase 1.1 Reduces Neuronal Excitability and Protects against Seizures through Upregulation of the M-Current.
- Authors
Miranda, Pablo; Cadaveira-Mosquera, Alba; González-Montelongo, Rafaela; Villarroel, Alvaro; González-Hernández, Tomás; Lamas, J. Antonio; de la Rosa, Diego Alvarez; Giraldez, Teresa
- Abstract
The M-current formed by tetramerization of Kv7.2 and Kv7.3 subunits is a neuronal voltage-gated K+ 1 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 (PIP2) and is distinctly localized to the plasma membrane (Arteaga et al., 2008). An SGK1.1 mutant with disrupted PIP2 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.
- Subjects
NEURAL circuitry; SERUM; GLUCOCORTICOIDS; KINASES; MEMBRANE potential; PHOSPHOINOSITIDES; MUTANT proteins
- Publication
Journal of Neuroscience, 2013, Vol 33, Issue 6, p2684
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.3442-12.2013