The serum- and glucocorticoid-inducible kinase-1 (SGK1) is ubiquitously expressed and under genomic control by cell stress (including cell shrinkage) and hormones (including gluco- and mineralocorticoids). Similar to its isoforms SGK2 and SGK3, SGK1 is activated by insulin and growth factors via phosphatidylinositol 3-kinase and the 3-phosphoinositide-dependent kinase PDK1. SGKs activate ion channels (e.g., ENaC, TRPV5, ROMK, Kv1.3, KCNE1/KCNQ1, GluR1, GluR6), carriers (e.g., NHE3, GLUT1, SGLT1, EAAT1-5), and the Na+-K+-ATPase. They regulate the activity of enzymes (e.g., glycogen synthase kinase-3, ubiquitin ligase Nedd4-2, phosphomannose mutase-2) and transcription factors (e.g., forkhead transcription factor FKHRL1, beta-catenin, nuclear factor kappaB). SGKs participate in the regulation of transport, hormone release, neuroexcitability, cell proliferation, and apoptosis. SGK1 contributes to Na+ retention and K+ elimination of the kidney, mineralocorticoid stimulation of salt appetite, glucocorticoid stimulation of intestinal Na+/H+ exchanger and nutrient transport, insulin-dependent salt sensitivity of blood pressure and salt sensitivity of peripheral glucose uptake, memory consolidation, and cardiac repolarization. A common ( approximately 5% prevalence) SGK1 gene variant is associated with increased blood pressure and body weight. SGK1 may thus contribute to metabolic syndrome. SGK1 may further participate in tumor growth, neurodegeneration, fibrosing disease, and the sequelae of ischemia. SGK3 is required for adequate hair growth and maintenance of intestinal nutrient transport and influences locomotive behavior. In conclusion, the SGKs cover a wide variety of physiological functions and may play an active role in a multitude of pathophysiological conditions. There is little doubt that further targets will be identified that are modulated by the SGK isoforms and that further SGK-dependent in vivo physiological functions and pathophysiological conditions will be defined.

Schizophrenia is a complex disorder, where family, twin and adoption studies have been demonstrating a high heritability of the disease and that this disease is not simply defined by several major genes but rather evolves from addition or potentiation of a specific cluster of genes, which subsequently determines the genetic vulnerability of an individual. Linkage and association studies suggest that a genetic vulnerablility, is not forcefully leading to the disease since triggering factors and environmental influences, i.e. birth complications, drug abuse, urban background or time of birth have been identified. This has lead to the assumption that schizophrenia is not only a genetically defined static disorder but a dynamic process leading to dysregulation of multiple pathways. There are several different hypothesis based on several facets of the disease, some of them due to the relatively well-known mechanisms of therapeutic agents. The most widely considered neurodevelopmental hypothesis of schizophrenia integrates environmental influences and causative genes. The dopamine hypothesis of schizophrenia is based on the fact that all common treatments involve antidopaminergic mechanisms and genes such as DRD2, DRD3, DARPP-32, BDNF or COMT are closely related to dopaminergic system functioning. The glutamatergic hypothesis of schizophrenia lead recently to a first successful mGlu2/3 receptor agonistic drug and is underpinned by significant findings in genes regulating the glutamatergic system (SLC1A6, SLC1A2 GRIN1, GRIN2A, GRIA1, NRG1, ErbB4, DTNBP1, DAAO, G72/30, GRM3). Correspondingly, GABA has been proposed to modulate the pathophysiology of the disease which is represented by the involvement of genes like GABRA1, GABRP, GABRA6 and Reelin. Moreover, several genes implicating immune, signaling and networking deficits have been reported to be involved in the disease, i.e. DISC1, RGS4, PRODH, DGCR6, ZDHHC8, DGCR2, Akt, CREB, IL-1B, IL-1RN, IL-10, IL-1B. However, molecular findings suggest that a complex interplay between receptors, kinases, proteins and hormones is involved in schizophrenia. In a unifying hypothesis, different cascades merge into another that ultimately lead to the development of symptoms adherent to schizophrenic disorders.

Abstract-Stress-dependent regulation of cardiac action potential duration is mediated by the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis. It is accompanied by an increased magnitude of the slow outward potassium ion current, I Ks . KCNQ1 and KCNE1 subunits coassemble to form the I Ks channel. Mutations in either subunit cause long QT syndrome, an inherited cardiac arrhythmia associated with an increased risk of sudden cardiac death.Here we demonstrate that exocytosis of KCNQ1 proteins to the plasma membrane requires the small GTPase RAB11, whereas endocytosis is dependent on RAB5. We further demonstrate that RAB-dependent KCNQ1/KCNE1 exocytosis is enhanced by the serum-and glucocorticoid-inducible kinase 1, and requires phosphorylation and activation of phosphoinositide 3-phosphate 5-kinase and the generation of PI(3,5)P 2 . Identification of KCNQ1/KCNE1 recycling and its modulation by serum-and glucocorticoid-inducible kinase 1-phosphoinositide 3-phosphate 5-kinase -PI(3,5)P 2 provides a mechanistic insight into stress-induced acceleration of cardiac repolarization. (Circ Res. 2007;100:686-692.)Key Words: kinase Ⅲ PIP2 Ⅲ RAB Ⅲ trafficking Ⅲ PIKfyve E motional stress activates the sympathetic nervous system 1 and the release of stress hormones such as cortisol via the hypothalamic-pituitary-adrenal (HPA) axis 2 and is a common trigger of sudden cardiac death. 3,4 One of the many genes regulated by cortisol is the serum-and glucocorticoidinducible kinase 1 (SGK1). 5,6 In vitro experiments have shown that SGK1 stimulates I Ks 7 , a repolarizing potassium current conducted by channels composed of KCNQ1 ␣-subunits and KCNE1 ␤-subunits. 8,9 Moreover, a gain-offunction variant of SGK1 is associated with shortening of the QT interval. 10 SGK1-mediated regulation of I Ks might be particularly important in patients with KCNQ1 (Kv7.1, Kv-LQT1) or KCNE1 (minK) mutations that are prone to fatal cardiac arrhythmias triggered by physical and psychological stress. 4 The mechanism responsible for regulation of I Ks channels by SGK1 have remained elusive. SGK1 enhances the abundance of other types of channel protein in the plasma membrane by inhibiting the ubiquitin ligase Nedd4 -2 11 in addition to other mechanisms (summarized by Lang et al 2006 12 ).Other candidate signaling molecules that may affect channel trafficking include RAB family proteins, GTPases involved in vesicle cycling. [13][14][15][16][17][18] RAB5, a monomeric GTPase of the Ras superfamily, has been implicated in the regulation of early steps in the endocytic pathway, whereas the RAB11 GTPase is localized at the trans-Golgi network, post-Golgi vesicles and the recycling endosome. 19 Both RAB5 and RAB11 are expressed in cardiac tissue. 17 Mammalian cells and Xenopus laevis oocytes have been shown to possess and use highly conserved RAB-dependent trafficking pathways. 20,21 Endocytosis by RAB5 and exocytosis by RAB11 have been reported to participate in the regulation of CFTR chloride channels 22 and the glucose transporter GluT4. 15...

The present brief review highlights the putative role of the serum-and glucocorticoid-inducible-kinase-1 (SGK1) in the regulation of neuronal function. SGK1 is genomically upregulated by cell shrinkage and by a variety of hormones including mineralocorticoids and glucocorticoids. The kinase is activated by insulin and growth factors via phosphatidylinositide-3-kinase (PI3-kinase), phosphoinositide-dependent kinase PDK1 and mammalian target of rapamycin mTORC2. SGK1 upregulates ion channels (e.g. SCN5A, ENaC, ASIC1, TRPV5,6, ROMK, Kv1.1-5, KCNEx/KCNQ1-5, GluR6, VSOAC, ClC2, CFTR), carriers (e.g. NHE3, NKCC2, NCC, NaPiIIb, SMIT, GLUT1,4, SGLT1, NaDC, EAAT1-5, SN1, ASCT2, 4F2/LAT, PepT2), and the Na + /K + -ATPase. SGK1 regulates enzymes (e.g. glycogen-synthase-kinase-3, ubiquitin-ligase Nedd4-2, phosphomannose-mutase-2), and transcription factors (e.g. forkhead transcription factor Foxo3a, β-catenin, nuclear factor-kappa-B (NFκB)). SGK1 participates in the regulation of transport, hormone release, neuroexcitability, inflammation, coagulation, cell proliferation and apoptosis. SGK1 contributes to regulation of renal Na + retention, renal K + elimination, salt appetite, gastric acid secretion, intestinal Na + /H + exchange and nutrient transport, insulin-dependent salt sensitivity of blood pressure, salt sensitivity of peripheral glucose uptake, cardiac repolarization and memory consolidation. Presumably, SGK1 contributes to the regulation of diverse cerebral functions (e.g. memory consolidation, fear retention) and the pathophysiology of several cerebral diseases (e.g. Parkinson's disease, schizophrenia, depression, Alzheimer's disease). Despite multiple SGK1 functions, the phenotype of the SGK1 knockout mouse is mild and becomes only apparent under challenging conditions.

ObjectiveAutoimmune encephalitis is most frequently associated with anti‐NMDAR autoantibodies. Their pathogenic relevance has been suggested by passive transfer of patients' cerebrospinal fluid (CSF) in mice in vivo. We aimed to analyze the intrathecal plasma cell repertoire, identify autoantibody‐producing clones, and characterize their antibody signatures in recombinant form.MethodsPatients with recent onset typical anti‐NMDAR encephalitis were subjected to flow cytometry analysis of the peripheral and intrathecal immune response before, during, and after immunotherapy. Recombinant human monoclonal antibodies (rhuMab) were cloned and expressed from matching immunoglobulin heavy‐ (IgH) and light‐chain (IgL) amplicons of clonally expanded intrathecal plasma cells (cePc) and tested for their pathogenic relevance.ResultsIntrathecal accumulation of B and plasma cells corresponded to the clinical course. The presence of cePc with hypermutated antigen receptors indicated an antigen‐driven intrathecal immune response. Consistently, a single recombinant human GluN1‐specific monoclonal antibody, rebuilt from intrathecal cePc, was sufficient to reproduce NMDAR epitope specificity in vitro. After intraventricular infusion in mice, it accumulated in the hippocampus, decreased synaptic NMDAR density, and caused severe reversible memory impairment, a key pathogenic feature of the human disease, in vivo.InterpretationA CNS‐specific humoral immune response is present in anti‐NMDAR encephalitis specifically targeting the GluN1 subunit of the NMDAR. Using reverse genetics, we recovered the typical intrathecal antibody signature in recombinant form, and proved its pathogenic relevance by passive transfer of disease symptoms from man to mouse, providing the critical link between intrathecal immune response and the pathogenesis of anti‐NMDAR encephalitis as a humorally mediated autoimmune disease.

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Accessory β-subunits of the KCNE gene family modulate the function of various cation channel α-subunits by the formation of heteromultimers. Among the most dramatic changes of biophysical properties of a voltage-gated channel by KCNEs are the effects of KCNE1 on KCNQ1 channels. KCNQ1 and KCNE1 are believed to form nativeI_Ks channels. Here, we characterize molecular determinants of KCNE1 interaction with KCNQ1 channels by scanning mutagenesis, double mutant cycle analysis, and molecular dynamics simulations. Our findings suggest that KCNE1 binds to the outer face of the KCNQ1 channel pore domain, modifies interactions between voltage sensor, S4-S5 linker and the pore domain, leading to structural modifications of the selectivity filter and voltage sensor domain. Molecular dynamics simulations suggest a stable interaction of the KCNE1 transmembrane α-helix with the pore domain S5/S6 and part of the voltage sensor domain S4 of KCNQ1 in a putative pre-open channel state. Formation of this state may induce slow activation gating, the pivotal characteristic of native cardiac I_Ks channels. This new KCNQ1-KCNE1 model may become useful for dynamic modeling of disease-associated mutant I_Ks channels.

␣-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPARs) are a major subtype of ionotropic glutamate receptors (iGluRs) that mediate rapid excitatory synaptic transmission in the vertebrate brain. Putative AMPARs are also expressed in the nervous system of invertebrates. In Caenorhabditis elegans, the GLR-1 receptor subunit is expressed in neural circuits that mediate avoidance behaviors and is required for glutamate-gated current in the AVA and AVD interneurons. Glutamate-gated currents can be recorded from heterologous cells that express vertebrate AMPARs; however, when C. elegans GLR-1 is expressed in heterologous cells, little or no glutamate-gated current is detected. This finding suggests that other receptor subunits or auxiliary proteins are required for function. Here, we identify Ce STG-1, a C. elegans stargazin-like protein, and show that expression of Ce STG-1 together with GLR-1 and the CUB-domain protein SOL-1 reconstitutes glutamate-gated currents in Xenopus oocytes. Ce STG-1 and homologues cloned from Drosophila (Dro STG1) and Apis mellifera (Apis STG1) have evolutionarily conserved functions and can partially substitute for one another to reconstitute glutamate-gated currents from rat, Drosophila, and C. elegans. Furthermore, we show that Ce STG-1 and Apis STG1 are primarily required for function independent of possible roles in promoting the surface expression of invertebrate AMPARs.C. elegans ͉ SOL-1 ͉ transmembrane AMPA receptor regulatory protein (TARP) ͉ GLR-1