title: The neuronal-specific SGK1.1 kinase regulates {delta}-epithelial Na+ channel independently of PY motifs and couples it to phospholipase C signaling.
abstract: The δ-subunit of the epithelial Na(+) channel (ENaC) is expressed in neurons of the human and monkey central nervous system and forms voltage-independent, amiloride-sensitive Na(+) channels when expressed in heterologous systems. It has been proposed that δ-ENaC could affect neuronal excitability and participate in the transduction of ischemic signals during hypoxia or inflammation. The regulation of δ-ENaC activity is poorly understood. ENaC channels in kidney epithelial cells are regulated by the serum- and glucocorticoid-induced kinase 1 (SGK1). Recently, a new isoform of this kinase (SGK1.1) has been described in the central nervous system. Here we show that δ-ENaC isoforms and SGK1.1 are coexpressed in pyramidal neurons of the human and monkey (Macaca fascicularis) cerebral cortex. Coexpression of δβγ-ENaC and SGK1.1 in Xenopus oocytes increases amiloride-sensitive current and channel plasma membrane abundance. The kinase also exerts its effect when δ-subunits are expressed alone, indicating that the process is not dependent on accessory subunits or the presence of PY motifs in the channel. Furthermore, SGK1.1 action depends on its enzymatic activity and binding to phosphatidylinositol(4,5)-bisphosphate. Physiological or pharmacological activation of phospholipase C abrogates SGK1.1 interaction with the plasma membrane and modulation of δ-ENaC. Our data support a physiological role for SGK1.1 in the regulation of δ-ENaC through a pathway that differs from the classical one and suggest that the kinase could serve as an integrator of different signaling pathways converging on the channel.
authors.affiliation: Unidad de Investigacion, Hospital Universitario Ntra Sra Candelaria, Ctra Rosario 145, Santa Cruz de Tenerife, Spain.
authors.forename: Diana
authors.initials: D
authors.lastname: Wesch
authors.forename: Pablo
authors.initials: P
authors.lastname: Miranda
authors.forename: Domingo
authors.initials: D
authors.lastname: Afonso-Oramas
authors.forename: Mike
authors.initials: M
authors.lastname: Althaus
authors.forename: Javier
authors.initials: J
authors.lastname: Castro-Hernández
authors.forename: Jaime
authors.initials: J
authors.lastname: Dominguez
authors.forename: Rory E
authors.initials: RE
authors.lastname: Morty
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Clauss
authors.forename: Tomás
authors.initials: T
authors.lastname: González-Hernández
authors.forename: Diego
authors.initials: D
authors.lastname: Alvarez de la Rosa
authors.forename: Teresa
authors.initials: T
authors.lastname: Giraldez
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D002540:Cerebral Cortex / Q000166:cytology; D053503:Epithelial Sodium Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D008252:Macaca fascicularis; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009474:Neurons / Q000166:cytology / Q000201:enzymology*; D009865:Oocytes / Q000166:cytology / Q000502:physiology; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D015398:Signal Transduction / Q000502:physiology*; D010738:Type C Phospholipases / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D053503:Epithelial Sodium Channels; D017874:Immediate-Early Proteins; D020033:Protein Isoforms; D017346:Protein Serine-Threonine Kinases; D010738:Type C Phospholipases; D000099184:Serum-Glucocorticoid Regulated Kinases