TY  - JOUR
AU  - Miranda, P.
AU  - Cadaveira-Mosquera, A.
AU  - González-Montelongo, R.
AU  - Villarroe, A.
AU  - González-Hernández, T.
AU  - Lamas, J.A.
AU  - de la Rosa, D.A.
AU  - Giraldez, T.
T1  - The neuronal serum- and glucocorticoid-regulated kinase 1.1 reduces neuronal excitability and protects against seizures through upregulation of the M-current
LA  - eng
PY  - 2013
SP  - 2684
EP  - 2696
T2  - Journal of Neuroscience
SN  - 0270-6474
VL  - 33
IS  - 6
AB  - 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 (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. © 2013 the authors.
DO  - 10.1523/JNEUROSCI.3442-12.2013
UR  - https://portalciencia.ull.es/documentos/5e39b7652999523aa92712cb
DP  - Dialnet - Portal de la Investigación
ER  -