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. 2010 Jun 7;588(Pt 18):3349–3354. doi: 10.1113/jphysiol.2010.190926

Significance of SGK1 in the regulation of neuronal function

Florian Lang 1, Nathalie Strutz-Seebohm 2, Guiscard Seebohm 2, Undine E Lang 3
PMCID: PMC2988501  PMID: 20530112

Abstract

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.

Florian Lang studied in Munich and Glasgow and received his MD in Munich. Prior to joining the department of physiology in Tübingen, he worked at the University of Munich, the University of Innsbruck (Austria), the Mayo Clinic (Rochester, MN, USA), the Max Planck Institute (Frankfurt, Germany), Yale University (New Haven, CT, USA) and the University of Naples (Italy). His research interests include properties, regulation and (patho)physiological significance of ion channels and transporters across the cell membrane. Functions in his focus include epithelial transport, blood pressure, metabolism, cell volume, cell proliferation, cell death, migration, inflammation and host–pathogen interaction.

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The serum- and glucocorticoid-inducible kinase was originally cloned as an early gene upregulated by the treatment of mammary tumour cells with glucocorticoids and serum (Firestone et al. 2003). Later the gene was discovered as a cell volume-regulated gene (Lang et al. 2006). Within some 20 min, osmotic and isotonic cell shrinkage profoundly upregulates the SGK1 expression (Lang et al. 2006). Presumably due to cell volume sensitivity of SGK1 transcription, cerebral SGK1 expression is further upregulated by dehydration (Lang et al. 2006). The hydration state of the brain is in turn a critical determinant of neuronal function (De Luca et al. 2010; Thornton, 2010). Hyperosmolar states decrease and hyposmolar states increase the susceptibility to epileptic seizures (Osehobo & Andrew, 1993; Ochoa, 2004), effects in part due to an osmotic gradient across the blood–brain barrier, leading to respective movements of water and changes of extracellular space (Cserr et al. 1991; Silver et al. 1996; Verkman, 2005). During osmotic cell swelling, excitability could be enhanced by the decrease of extracellular space (Osehobo & Andrew, 1993). Hydration may further modify cerebral function by influencing neuronal or glial cell volume (Lang et al. 1998). Dehydration alters the expression of a wide variety of genes (Mutsuga et al. 2005; Lee et al. 2006; Ramos et al. 2007; Hindmarch et al. 2008; Wang et al. 2009; Bourassa & Speth, 2010; Brocker et al. 2010; Pereira-Derderian et al. 2010; Scott & Brown, 2010) including SGK1 (Lang et al. 2006).

SGK1-sensitive functions presumably contribute significantly to altered function of the dehydrated brain. Beyond that multiple additional physiological and pathophysiological regulators of SGK1 expression and function are known which may modify cerebral function in the absence of neuronal or glial cell volume changes. The present brief review amplifies on the role of SGK1 in the regulation of neuronal cell function. Due to N limitations of references, reviews are quoted covering earlier papers.

Regulation and function of SGK1

SGK1 transcription is controlled by a wide variety of additional hormones and further regulators including increase of cytosolic Ca2+ activity and NO (Lang et al. 2006, 2009). SGK1 is ubiquitously expressed (Lang et al. 2006, 2009). The kinase is activated by insulin and growth factors via PI3-kinase, the 3-phosphoinositide-dependent kinase PDK1, and the mammalian target of rapamycin mTORC2 (Lang et al. 2006, 2009; Peterson et al. 2009).

SGK1 increases the protein abundance and/or activity of a variety of ion channels (e.g. SCN5A, ENaC, ASIC1, TRPV5,6, ROMK, Kv1.1–5, KCNE1/KCNQ1, KCNQ2–5, GluR6, VSOAC, ClC2, CFTR), carriers (e.g. NHE3, NKCC2, NCC, NaPiIIb, SMIT, GLUT1,4, SGLT1, NaDC, EAAT1–5, SN1, ASCT2, 4F2/LAT, PepT2, CreaT), and the Na+/K+-ATPase (Lang et al. 2006, 2009; Boehmer et al. 2008a,b; Schuetz et al. 2008; Gehring et al. 2009; Krueger et al. 2009; Laufer et al. 2009). Several of the carriers could contribute to regulatory cell volume increase (RVI), such as NHE, NKCC or SMIT (Lang et al. 1998; Hoffmann et al. 2009). Thus, upregulation of SGK1 by cell shrinkage may support RVI. Stimulation of K+ channels and Cl− channels, however, would counteract RVI and rather support regulatory cell volume decrease (RVD) (Lang et al. 1998; Hoffmann et al. 2009). SGK1 presumably enhances the cellular capacity for both RVI and RVD but is presumably not involved in the rapid activation of cell volume regulatory mechanisms, which is accomplished by activation of other kinases.

SGK1 regulates several enzymes (e.g. glycogensynthase-kinase-3, ubiquitin-ligase Nedd4-2, phosphomannose-mutase-2) and transcription factors (e.g. FKHRL1/Foxo3a, β-catenin, NFκB, p53) (Lang et al. 2006, 2009). SGK1 contributes to the regulation of transport, hormone release, neuroexcitability, inflammation, cell proliferation and apoptosis (Lang et al. 2006, 2009).

SGK1 further participates in the regulation of renal Na+ retention and renal K+ elimination, mineralocorticoid stimulation of salt appetite, glucocorticoid stimulation of gastric acid secretion, intestinal mineral, electrolyte and nutrient transport, blood coagulation, insulin-dependent salt sensitivity of blood pressure and salt sensitivity of peripheral glucose uptake (Lang et al. 2006, 2009). A common (∼3–5% prevalence in Caucasians, ∼10% in Africans) SGK1 gene variant is associated with increased blood pressure, obesity, enhanced prevalence of diabetes and a shortening of the cardiac action potential (Lang et al. 2006, 2009). SGK1 is further involved in the pathophysiology of allergy, peptic ulcer, tumour growth, fibrosing disease, ischaemia and neurodegeneration (Lang et al. 2006, 2009).

The phenotype of SGK1 knockout mice is surprisingly mild and becomes only apparent upon appropriate stress conditions.

Putative role of SGK1 in neuronal function

Cerebral SGK1 is upregulated by glucocorticoids (Sato et al. 2008; Sarabdjitsingh et al. 2010), corticotropin releasing hormone (Sheng et al. 2008), hyperactivity (Kalinichev et al. 2008), intracranial self-stimulation (Huguet et al. 2009), chronic escalating morphine regimen (Befort et al. 2008) and administration of the antipsychotic drug clozapine (Robbins et al. 2008). Hippocampal SGK1 expression is stimulated by fear conditioning, elevated plus maze exposure and after enrichment training (Lang et al. 2006). SGK1 transcript levels are further enhanced by the psychostimulant amphetamine, by the hallucinogenic drug lysergic acid dimethylamide (LSD), by neuronal injury, neuronal excitotoxicity and microgravity (Lang et al. 2006). Neuronal SGK1 expression is suppressed by Zif268 (Egr1/Krox24/NGF-IA), a transcription factor associated with neuronal plasticity (James et al. 2006). Hypothalamic SGK1 is upregulated by fasting or obesity with hyperphagia (Nonogaki et al. 2006).

SGK1 is considered to play an important role in long-term memory formation (Ma et al. 2006). SGK1 phosphorylation increases after tetanization (Ma et al. 2006) and transfection of constitutively active SGK1 upregulates postsynaptic density-95 expression in the hippocampus and impairs the expression, but not the induction, of long-term potentiation (Ma et al. 2006). Transfection of wild-type SGK1 improves, and transfection of inactive SGK1 decreases, the learning abilities of rats (Lang et al. 2006). In those animals transfection of inactive SGK1 impairs spatial learning, fear-conditioning learning, and novel object recognition learning (Lang et al. 2006). Moreover, hippocampal SGK1 mRNA abundance is increased in fast-learning when compared to slow-learning rats (Lang et al. 2006).

Transfection of inactive SGK1 to hippocampal neurons further impaired, whereas transfection of constitutively active SGK1 enhanced, fear retention (Lee et al. 2007). SGK1 downregulates Hairy and Enhancer of split 5 (Hes5) resulting in enhanced fear retention, whereas over-expression of Hes5 negatively regulates contextual fear memory formation (Lee et al. 2007). SGK1 stimulates dendrite growth, which may impact on learning abilities (Lang et al. 2006).

The role of SGK1 in memory consolidation may further relate to its effect on glutamate receptors. SGK isoforms upregulate AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolic acid) and kainate receptors and are thus expected to enhance the excitatory effects of glutamate (Lang et al. 2006, 2009). The kainate receptor is particularly important for synaptic transmission and plasticity in the hippocampus (Dargan & Amici, 2009). SGK1 contributes to the glucocorticoid stimulation of cerebral GluR6 expression (Lang et al. 2006). Accordingly, SGK1 participates in the neuronal effects of glucocorticoids, which enhance the neuronal responsiveness but by the same token favour neurotoxicity (Lang et al. 2006). On the other hand, SGK1 stimulates glutamate transporters (Lang et al. 2006), which clear the synaptic clefts from glutamate and thus terminate excitation (Benarroch, 2010).

SGK phosphorylates guanosine nucleotide dissociation inhibitor (GDI) thus increasing the formation of GDI-Rab4 complexes, which facilitate the Rab4-mediated recycling of AMPARs to the synaptic membrane (Liu et al. 2010).

SGK1-mediated spatial memory facilitation and neuronal plasticity may further involve phosphorylation of IKKα with subsequent stimulation of NFκB and triggering of NFκB-dependent expression of genes such as NR2A and NR2B (Tai et al. 2009).

In addition, SGK1 could modify excitation by regulating Kv channels (Lang et al. 2006, 2009), which participate in the maintenance of neuronal membrane potential (Pongs, 2008).

SGK1 presumably participates in the signalling of brain-derived neurotrophic factor (BDNF), which stimulates the PI3-kinase and thus probably SGK1 (Lang et al. 2006). BDNF influences neuronal survival, plasticity, mood and long-lasting memory formation (Lang et al. 2006). PI3-kinase mediates the BDNF-dependent spatial memory formation in rats (Lang et al. 2006).

Hypothalamic SGK1 presumably participates in the regulation of food intake (Nonogaki et al. 2006).

Putative role of SGK1 in neuronal disease

Lack of SGK may blunt the glutamate action but at the same time decrease glutamate clearance from the synaptic cleft. As glutamate may exert neurotoxic effects (Lau & Tymianski, 2010), altered function or regulation of glutamate transporters and glutamate receptors may influence neuroexcitotoxicity.

Decreased expression of glutamate transporters favours extracellular glutamate accumulation, excitotoxicity and eventually neuronal cell death (Rothstein et al. 1996). Loss of EAAT2 function may contribute to amyotrophic lateral sclerosis (ALS); loss of EAAT4 function correlates with loss of Purkinje cells during ischaemia and defective glutamate transport may contribute to retinopathy following glaucoma or to diabetic retinopathy (Lang et al. 2006). Whether or not decreased stimulation of the carriers by SGK1 leads to pathophysiologically relevant decline of transporter function remains to be shown.

AMPA receptor upregulation contributes to ischaemic-induced cell death (Lang et al. 2006). AMPA and kainate receptors further participate in the pathophysiology of ALS and schizophrenia (Lang et al. 2006). Deranged function of GluR3 is involved in the autoimmune disease Rasmussen's encephalitis, a disorder leading to inflammation of the brain, severe epilepsy, hemiplegia and dementia (Lang et al. 2006). Upregulation of kainate receptors supports epileptic activity (Lang et al. 2006). Deranged SGK1-dependent regulation of AMPA or kainate receptors could, at least in theory, participate in the pathophysiology of those diseases.

Beyond its effects on glutamate receptors and carriers, SGK1 influences further carriers relevant for neuronal function, such as the creatine transporter CreaT (Lang et al. 2006). Individuals with defective CreaT suffer from mental retardation (Lang et al. 2006). SGK1 upregulates the inositol transporter SMIT (Klaus et al. 2008), which participates in neuronal cell volume regulation (Lang et al. 1998).

SGK1 could contribute to the glucocorticoid effects during cerebral injury including stroke, seizure, or hypoglycaemia (Lang et al. 2006).

SGK isoforms participate in the signalling of brain-derived neurotrophic factor and could thus contribute to BDNF signalling in several neuropsychiatric disorders, such as schizophrenia, depression and Alzheimer's disease (Lang et al. 2006; Lang et al. 2007). SGK1 could further contribute to the effects of antidepressants, antipsychotic drugs and electroconvulsive treatment (Lang et al. 2006).

SGK1 phosphorylates tau and may thus contribute to the pathophysiology of Alzheimer's disease, which is paralleled by hyperphosphorylation of tau (Lang et al. 2006). Vascular and meningeal alterations similar to those in Alzheimer's disease are observed in transgenic mice over-expressing transforming growth factor beta (TGFβ), which is a powerful stimulator of SGK1 expression (Lang et al. 2006). On the other hand, TGFβ has been claimed to be neuroprotective by decreasing the accumulation of β-amyloid peptide (Lang et al. 2006)

SGK1 phosphorylates huntingtin and may thus counteract huntingtin toxicity (Lang et al. 2006; Warby et al. 2009).

SGK1 is further implicated in the pathophysiology of Parkinson's disease (Sakai et al. 2007). In a model of that disease, genomic upregulation of SGK1 coincides with the onset of dopaminergic cell death (Lang et al. 2006).

Enhanced SGK1 expression has been observed in Rett syndrome (RTT), a disorder with severe mental retardation (Lang et al. 2006).

SGK1 deficiency may participate in a major depressive disorder, which is frequently paralleled by insufficient glucocorticoid signalling (Sato et al. 2008). SGK1 may further be involved in anxiety disorders, as phosphatidylinositide-dependent kinase deficiency in mice increases anxiety and decreases GABA and serotonin abundance in the amygdala (Ackermann et al. 2008).

SGK1 transcription is enhanced during cerebral ischaemia (Lang et al. 2006) and several effects of SGK1 could facilitate cellular survival during energy deprivation. Stimulation of creatine uptake by the Na+-coupled creatine transporter CreaT (Lang et al. 2006), for instance, enhances the capacity to bind phosphate to creatine and thus increases the cellular ability to store rapidly available energy. Stimulation of the glucose transporter GLUT1 (Palmada et al. 2006) provides neurons with fuel for anaerobic glycolysis. During ischaemia, the stimulation of the Na+/K+-ATPase by SGK1 is a double-edged sword. On the one hand the stimulation of the energy-consuming Na+/K+-ATPase leads to acceleration of energy depletion. On the other hand, it counteracts the decline of pump activity and the subsequent cellular K+ loss, depolarization, entry of Cl− and cell swelling – known consequences of energy depletion.

Beyond its influence on transporters and stimulation of Na+/K+-ATPase, SGK1 inhibits apoptosis and thus prolongs cell survival by influencing several signalling pathways as described elsewhere (Lang et al. 2006, 2009).

As apparent from the SGK1 knockout mice (see above), the lack of SGK1 does not lead to profound derangements of neuronal function. Obviously, the SGK1-sensitive functions could be sufficiently stimulated by related kinases, such as the other SGK or Akt/PKB isoforms. However, under conditions leading to marked upregulation of SGK1 this kinase may take a leading part in the regulation of cerebral function.

In summary, compelling evidence suggests a role for SGKs in the pathophysiology of brain disease. However, it is not certain, to what extent SGK1 protects from or stimulates cell death or is just an innocent bystander in those disorders. Clearly, we are presently far from understanding the contribution of SGK1 to the deterioration or maintenance of neuronal function and additional experimental effort is needed to unravel the contribution of this multifunctional kinase to cerebral health and disease.

Glossary

Abbreviations

ALS

amyotrophic lateral sclerosis

BDNF

brain-derived neurotrophic factor

mTOR

mammalian target of rapamycin

NFκB

nuclear factor-kappa-B

PDK1

phosphoinositide-dependent kinase 1

PI3-kinase

phosphatidylinositide-3-kinase

SGK1

serum- and glucocorticoid-inducible kinase-1

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