Serine/threonine-protein kinase Sgk1 also known as serum and glucocorticoid-regulated kinase 1 is an enzyme that in humans is encoded by the SGK1 gene. SGK1 belongs to a subfamily of serine/threonine kinases that is under acute transcriptional control by several stimuli, including serum and glucocorticoids. The kinase is activated by insulin and growth factors via phosphatidylinositide-3-kinase, phosphoinositide-dependent protein kinase PDPK1 and mammalian target of rapamycin mTORC2. It has been shown to "regulate several enzymes and transcription factors; SGK1 contributes to the regulation of transport, hormone release, neuroexcitability, inflammation, cell proliferation and apoptosis". SGK1 increases the protein abundance and/or activity of a variety of ion channel, carriers, and the Na+/K+-ATPase. Over the past few years, there has been increasing evidence that SGK1 expression is regulated during both discrete developmental stages and pathological conditions such as hypertension, diabetic neuropathy, ischemia, trauma, and neurodegenerative diseases.
Function This gene encodes a serine/threonine protein kinase that plays an important role in cellular stress response. This kinase activates certain potassium, sodium, and chloride channels, suggesting an involvement in the regulation of processes such as cell survival, neuronal excitability, and renal sodium excretion.
Ion channel and transporter regulation SGK1 has been shown to regulate the following ion channels:
Epithelial Na+ channel ENaC Renal outer medullary K+ channel KCNJ1 (ROMK1) Renal epithelial Ca2+ channel TRPV5 Ubiquitous Cl− channel CLCN2 (ClC2) Cardiac voltage-gated Na+ channel SCN5A Cardiac and epithelial K+ channels KCNE1/KCNQ1 Voltage-gated K+ channels Kv1.3, Kv1.5, and Kv4.3 Glutamate Receptors The following carriers and pumps are influenced by SGK1:
Glucose Transporters Creatine Transporter SLC6A8 (CreaT) Phosphate Carrier
Regulation of cell volume SGK1 is upregulated by osmotic and isotonic cell shrinkage. "It is tempting to speculate that SGK1-dependent regulation of cation channels contributes to the regulation of cell volume, which involves cation channels in a variety of cells". The entrance of NaCl and osmotically driven water into cells leads to an increase in the cell's regulatory cell volume. This occurs as the entrance of Na+ depolarizes the cell, thus allowing the parallel entrance of Cl−. SGK1 has also been shown to increase the activity of cell volume-regulated Cl− channel ClC2. The activation of these Cl− channels result in the exit of Cl− and eventually the exit of K+, and the cellular loss of KCl results in a decrease of regulatory cell volume. However, the functional significance of SGK1 in cell volume regulation, along with its stimulation of cation channels, is still not clearly understood. "Moreover, the molecular identity of the cation channels and the mechanisms of their regulation by glucocorticoids and osmotic cell shrinkage have remained elusive". The following observations seem to have conflicting results, as one suggests a role of SGK1 by cell shrinkage and regulatory cell volume increase while the other suggests regulatory cell volume decrease. It is possible that SGK1 works to maintain regulatory cell volume by increasing the cell's ability to cope with alterations in cell volume.
Dehydration The hydration state of the brain is critical to neuronal function. One way hydration modifies cerebral function is by influencing neuronal and glial cell volume. Dehydration alters the expression of a wide variety of genes including SGK1. "It has been shown that SGK1-sensitive functions contribute significantly to the altered function of the dehydrated brain".
Cell proliferation and apoptosis SGK1 has been shown to inhibit apoptosis. "The antiapoptotic effect of SGK1 and SGK3 has been attributed in part to phosphorylation of forkhead transcription factors". It is suggested that proliferative signals transport SGK1 into the nucleus, and the effect of SGK1 on cell proliferation may be due to its ability to regulate Kv1.3. "The upregulation of Kv1.3 channel activity may be important for the proliferative effect of growth factors, as IGF-I induced cell proliferation is disrupted by several blockers of Kv channels". SGK1 knockout mice show seemingly normal development. "Thus SGK1 is either not a crucial element in the regulation of cell proliferation or apoptosis, or related kinase(s) can effectively replace SGK1 function in the SGK1 knockout mice".
Memory formation It has been suggested that this kinase plays a critical role in long-term memory formation. Wild-type SGK1 improves the learning abilities of rats. On the other hand, the transfection of inactive SGK1 decreases their abilities in spatial, fear-conditioning, and novel object recognition learning. The effect of glutamate receptors may also impact the role of SGK1 in memory consolidation. "SGK isoforms upregulate AMPA and kainate receptors and thus are expected to enhance the excitatory effects of glutamate". Synaptic transmission and hippocampal plasticity are both affected by kainate receptors. A lack of SGK may reduce glutamate clearance from the synaptic cleft leading to altered function or regulation of glutamate transporters and receptors; This could result in increasing neuroexcitotoxicity and eventually neuronal cell death.
Long-term potentiation SGK has been to shown to facilitate the expression of long-term potentiation in hippocampal neurons and neuronal plasticity. SGK mRNA expression in the hippocampus in enhanced by the AMPA receptor. Moreover, "AMPA receptor-mediated synaptic transmission is closely associated with the late phase of long-term potentiation".
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