title: The neuronal serum- and glucocorticoid-regulated kinase 1.1 reduces neuronal excitability and protects against seizures through upregulation of the M-current.
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.
authors: Research Unit, University Hospital NS Candelaria, 38010 Santa Cruz de Tenerife, Spain.
authors: Pablo
authors: P
authors: Miranda
authors: Alba
authors: A
authors: Cadaveira-Mosquera
authors: Rafaela
authors: R
authors: González-Montelongo
authors: Alvaro
authors: A
authors: Villarroel
authors: Tomás
authors: T
authors: González-Hernández
authors: J Antonio
authors: JA
authors: Lamas
authors: Diego
authors: D
authors: Alvarez de la Rosa
authors: Teresa
authors: T
authors: Giraldez
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D017874:Immediate-Early Proteins / Q000096:biosynthesis*; D051658:KCNQ2 Potassium Channel / Q000378:metabolism; D051659:KCNQ3 Potassium Channel / Q000378:metabolism; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000201:enzymology*; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis*; D012640:Seizures / Q000201:enzymology* / Q000517:prevention & control*; D015854:Up-Regulation / Q000502:physiology*; D014982:Xenopus laevis; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D017874:Immediate-Early Proteins; D051658:KCNQ2 Potassium Channel; D051659:KCNQ3 Potassium Channel; D017346:Protein Serine-Threonine Kinases; D000099184:Serum-Glucocorticoid Regulated Kinases
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