SGK1
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Serine/threonine-protein kinase Sgk1 also known as serum and glucocorticoid-regulated kinase 1 is an
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
that in humans is encoded by the SGK1
gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
. SGK1 belongs to a subfamily of serine/threonine kinases that is under acute transcriptional control by several stimuli, including serum and
glucocorticoid Glucocorticoids (or, less commonly, glucocorticosteroids) are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebr ...
s. The kinase is activated by
insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism o ...
and growth factors via phosphatidylinositide-3-kinase, phosphoinositide-dependent kinase PDK1 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 Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...
,
cell proliferation Cell proliferation is the process by which ''a cell grows and divides to produce two daughter cells''. Cell proliferation leads to an exponential increase in cell number and is therefore a rapid mechanism of tissue growth. Cell proliferation re ...
and
apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
". SGK1 increases the protein abundance and/or activity of a variety of
ion channel Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of io ...
, carriers, and the
Na+/K+-ATPase NA, N.A., Na, nA or n/a may refer to: Chemistry and physics * Sodium, symbol Na, a chemical element * Avogadro constant (''N''A) * Nucleophilic addition, a type of reaction in organic chemistry * Numerical aperture, a number that characterizes ...
. 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 Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high bl ...
,
diabetic neuropathy Diabetic neuropathy is various types of nerve damage associated with diabetes mellitus. Symptoms depend on the site of nerve damage and can include motor changes such as weakness; sensory symptoms such as numbness, tingling, or pain; or autonomic c ...
,
ischemia Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems wi ...
,
trauma Trauma most often refers to: * Major trauma, in physical medicine, severe physical injury caused by an external source * Psychological trauma, a type of damage to the psyche that occurs as a result of a severely distressing event *Traumatic i ...
, and
neurodegenerative diseases A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic ...
.


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 channel Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of io ...
s: *Epithelial Na+ channel
ENaC The epithelial sodium channel (ENaC), (also known as amiloride-sensitive sodium channel) is a membrane-bound ion channel that is selectively permeable to sodium ions (). It is assembled as a heterotrimer composed of three homologous subunits α ...
*Renal outer medullary K+ channel
KCNJ1 The renal outer medullary potassium channel (ROMK) is an ATP-dependent potassium channel (Kir1.1) that transports potassium out of cells. It plays an important role in potassium recycling in the thick ascending limb (TAL) and potassium secretion ...
(ROMK1) *Renal epithelial Ca2+ channel
TRPV5 Transient receptor potential cation channel subfamily V member 5 is a calcium channel protein that in humans is encoded by the ''TRPV5'' gene. Function The ''TRPV5'' gene is a member of the transient receptor family and the TRPV subfamily. The ...
*Ubiquitous Cl channel
CLCN2 Chloride channel protein 2 is a protein that in humans is encoded by the ''CLCN2'' gene. Mutations of this gene have been found to cause leukoencephalopathy and Idiopathic generalised epilepsy (), although the latter claim has been disputed. CLCN2 ...
(ClC2) *Cardiac voltage-gated Na+ channel
SCN5A Sodium channel protein type 5 subunit alpha, also known as NaV1.5 is an integral membrane protein and tetrodotoxin-resistant voltage-gated sodium channel subunit. NaV1.5 is found primarily in cardiac muscle, where it mediates the fast influx of N ...
*Cardiac and epithelial K+ channels KCNE1/
KCNQ1 Kv7.1 (KvLQT1) is a potassium channel protein whose primary subunit in humans is encoded by the ''KCNQ1'' gene. Kv7.1 is a voltage and lipid-gated potassium channel present in the cell membranes of cardiac tissue and in inner ear neurons among o ...
*Voltage-gated K+ channels
Kv1.3 Potassium voltage-gated channel, shaker-related subfamily, member 3, also known as KCNA3 or Kv1.3, is a protein that in humans is encoded by the ''KCNA3'' gene. Potassium channels represent the most complex class of voltage-gated ion channels fro ...
,
Kv1.5 Potassium voltage-gated channel, shaker-related subfamily, member 5, also known as KCNA5 or Kv1.5, is a protein that in humans is encoded by the ''KCNA5'' gene. Function Potassium channels represent the most complex class of voltage-gated ion ...
, and
Kv4.3 Potassium voltage-gated channel subfamily D member 3 also known as Kv4.3 is a protein that in humans is encoded by the ''KCND3'' gene. It contributes to the cardiac transient outward potassium current (Ito1), the main contributing current to the r ...
*Glutamate Receptors The following carriers and pumps are influenced by SGK1: *Glucose Transporters *Creatine Transporter
SLC6A8 Sodium- and chloride-dependent creatine transporter 1 is a protein that in humans is encoded by the ''SLC6A8'' gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity ...
(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 Hydration may refer to: * Hydrate, a substance that contains water * Hydration enthalpy, energy released through hydrating a substance * Hydration reaction, a chemical addition reaction where a hydroxyl group and proton are added to a compound * ...
modifies cerebral function is by influencing neuronal and
glial cell Glia, also called glial cells (gliocytes) or neuroglia, are non-neuronal cells in the central nervous system (brain and spinal cord) and the peripheral nervous system that do not produce electrical impulses. They maintain homeostasis, form mye ...
volume.
Dehydration In physiology, dehydration is a lack of total body water, with an accompanying disruption of metabolic processes. It occurs when free water loss exceeds free water intake, usually due to exercise, disease, or high environmental temperature. Mil ...
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 Serine/threonine-protein kinase Sgk3 is an enzyme that in humans is encoded by the ''SGK3'' gene. Function This gene is a member of the serine/threonine protein kinase family and encodes a phosphoprotein with a PX (phox homology) domain. The ...
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 Cell proliferation is the process by which ''a cell grows and divides to produce two daughter cells''. Cell proliferation leads to an exponential increase in cell number and is therefore a rapid mechanism of tissue growth. Cell proliferation re ...
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 receptor Glutamate receptors are synaptic and non synaptic receptors located primarily on the membranes of neuronal and glial cells. Glutamate (the conjugate base of glutamic acid) is abundant in the human body, but particularly in the nervous system a ...
s may also impact the role of SGK1 in memory consolidation. "SGK isoforms upregulate
AMPA α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, better known as AMPA, is a compound that is a specific agonist for the AMPA receptor, where it mimics the effects of the neurotransmitter glutamate. There are several types of glutamatergic ...
and
kainate receptor Kainate receptors, or kainic acid receptors (KARs), are ionotropic receptors that respond to the neurotransmitter glutamate. They were first identified as a distinct receptor type through their selective activation by the agonist kainate, a drug ...
s and thus are expected to enhance the excitatory effects of glutamate". Synaptic transmission and hippocampal plasticity are both affected by
kainate receptor Kainate receptors, or kainic acid receptors (KARs), are ionotropic receptors that respond to the neurotransmitter glutamate. They were first identified as a distinct receptor type through their selective activation by the agonist kainate, a drug ...
s. 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 neuroscience, long-term potentiation (LTP) is a persistent strengthening of synapses based on recent patterns of activity. These are patterns of synaptic activity that produce a long-lasting increase in signal transmission between two neurons ...
in hippocampal neurons and neuronal plasticity. SGK
mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein. mRNA is ...
expression in the hippocampus in enhanced by the
AMPA receptor The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (also known as AMPA receptor, AMPAR, or quisqualate receptor) is an ionotropic receptor, ionotropic transmembrane receptor for glutamate (iGluR) that mediates fast synapse, synap ...
. Moreover, "
AMPA receptor The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (also known as AMPA receptor, AMPAR, or quisqualate receptor) is an ionotropic receptor, ionotropic transmembrane receptor for glutamate (iGluR) that mediates fast synapse, synap ...
-mediated synaptic transmission is closely associated with the late phase of
long-term potentiation In neuroscience, long-term potentiation (LTP) is a persistent strengthening of synapses based on recent patterns of activity. These are patterns of synaptic activity that produce a long-lasting increase in signal transmission between two neurons ...
".


Transcription

The human isoform of SGK1 has been identified as a cell volume-regulated gene that is transcriptionally upregulated by cell shrinkage. "The regulation of SGK1 transcript levels is fast; appearance and disappearance of SGK1 mRNA require <20 min". Its transcription is increasingly expressed by serum and glucocorticoids, and transcriptional changes in SGK1 expression occur in correlation with the appearance of cell death. Signaling molecules involved in transcriptional regulation of SGK1 include cAMP,
p53 p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...
, and
protein kinase C In cell biology, Protein kinase C, commonly abbreviated to PKC (EC 2.7.11.13), is a family of protein kinase enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and t ...
. As SGK1 transcription is sensitive to cell volume, cerebral SGK1 expression is upregulated by
dehydration In physiology, dehydration is a lack of total body water, with an accompanying disruption of metabolic processes. It occurs when free water loss exceeds free water intake, usually due to exercise, disease, or high environmental temperature. Mil ...
. "SGK1 expression is controlled by a large number of stimuli including serum, IFG-1,
oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily Detoxification, detoxify the reactive intermediates or to repair the resulting damage. Disturbances ...
,
cytokines Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
, hypotonic conditions, and
glucocorticoids Glucocorticoids (or, less commonly, glucocorticosteroids) are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebr ...
". Mineralocorticoids,
gonadotropin Gonadotropins are glycoprotein hormones secreted by gonadotropic cells of the anterior pituitary of vertebrates. This family includes the mammalian hormones follicle-stimulating hormone (FSH) and luteinizing hormone (LH), the placental/ chorioni ...
s, fibroblast and
platelet-derived growth factor Platelet-derived growth factor (PDGF) is one among numerous growth factors that regulate cell growth and division. In particular, PDGF plays a significant role in blood vessel formation, the growth of blood vessels from already-existing blood v ...
, and other
cytokine Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
s are also understood to stimulate SGK1 transcription. The upregulation of SGK1 in various neurodegenerative diseases correlates directly with these stimuli, as alterations in these stimuli accompany many neurodegenerative diseases. *Glucocorticoids: SGK expression is mainly regulated by
glucocorticoid Glucocorticoids (or, less commonly, glucocorticosteroids) are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebr ...
s. Glucocorticoids have been shown to enhance memory consolidation in a range of exercises in animals. Glucocorticoid hormones are also consistently increased in patients with
severe depression Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive low mood, low self-esteem, and loss of interest or pleasure in normally enjoyable activities. Introdu ...
. It has been shown that chronically high concentrations of glucocorticoids impair hippocampal
neurogenesis Neurogenesis is the process by which nervous system cells, the neurons, are produced by neural stem cells (NSCs). It occurs in all species of animals except the porifera (sponges) and placozoans. Types of NSCs include neuroepithelial cells (NECs) ...
by activating the
glucocorticoid receptor The glucocorticoid receptor (GR, or GCR) also known as NR3C1 (nuclear receptor subfamily 3, group C, member 1) is the receptor to which cortisol and other glucocorticoids bind. The GR is expressed in almost every cell in the body and regulates ...
(GR). Indeed, "SGK1 is a key enzyme involved in the downstream mechanisms by which glucocorticoids reduce neurogenesis and in the upstream potentiation and maintenance of GR function, even after glucocorticoid withdrawal". *Oxidative Stress:
Oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily Detoxification, detoxify the reactive intermediates or to repair the resulting damage. Disturbances ...
is a common component of the neurodegenerative process. "It has been shown to induce SGK expression through a p38/MAPK-dependent pathway, with SGK1 responding rapidly and transiently to changes in stress". *DNA Damage: "SGK1 gene transcription is stimulated by DNA damage through
p53 p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...
and activation of extracellular signal-regulated kinase (ERK1/2)". Other stimuli include neuronal injury, neuronal
excitotoxicity In excitotoxicity, nerve cells suffer damage or death when the levels of otherwise necessary and safe neurotransmitters such as glutamate become pathologically high, resulting in excessive stimulation of receptors. For example, when glutamate re ...
, increased cytosolic Ca2+ concentration,
ischemia Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems wi ...
, and
nitric oxide Nitric oxide (nitrogen oxide or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitric oxide is a free radical: it has an unpaired electron, which is sometimes denoted by a dot in its che ...
.


Metabolism

SGK1, along with
SGK3 Serine/threonine-protein kinase Sgk3 is an enzyme that in humans is encoded by the ''SGK3'' gene. Function This gene is a member of the serine/threonine protein kinase family and encodes a phosphoprotein with a PX (phox homology) domain. The ...
, has been shown to stimulate the absorption of intestinal glucose by the Na+-glucose cotransporter
SGLT1 Sodium/glucose cotransporter 1 (SGLT1) also known as solute carrier family 5 member 1 is a protein in humans that is encoded by the gene which encodes the production of the SGLT1 protein to line the absorptive cells in the small intestine and th ...
. "SGK1 also favors cellular glucose uptake from the circulation into several tissues including brain, fat, and skeletal muscle". SGK1 also plays a critical role in the stimulation of cellular glucose uptake by insulin. Accordingly, SGK1 does not only integrate effects of mineralocorticoids and insulin on renal tubular Na+ transport but similarly affects glucose transport".


Kidney

By
aldosterone Aldosterone is the main mineralocorticoid steroid hormone produced by the zona glomerulosa of the adrenal cortex in the adrenal gland. It is essential for sodium conservation in the kidney, salivary glands, sweat glands, and colon. It plays a c ...
,
insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism o ...
, and IGF-I, SGK1 has been suggested to influence the regulation of
ENaC The epithelial sodium channel (ENaC), (also known as amiloride-sensitive sodium channel) is a membrane-bound ion channel that is selectively permeable to sodium ions (). It is assembled as a heterotrimer composed of three homologous subunits α ...
and participate in the regulation of renal Na+ excretion. It has been indicated "that activation of ENaC by ADH or insulin depends on SGK1 and/or reflects independent pathways induced by ADH/insulin and SGK1 that converge on the same target structures". Renal ENaC function, along with renal mineralocorticoid action, is also partly dependent upon the presence of SGK1. One study also determined that SGK1 has a critical role in insulin-induced renal Na+ retention. "SGK1 plays at least a dual role in mineralocorticoid-regulated NaCl
homeostasis In biology, homeostasis (British English, British also homoeostasis) Help:IPA/English, (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physics, physical, and chemistry, chemical conditions maintained by organism, living systems. Thi ...
. SGK1 dependence of both NaCl intake and renal NaCl reabsorption suggests that excessive SGK1 activity leads to arterial
hypertension Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high bl ...
by simultaneous stimulation of oral NaCl intake and renal NaCl retention".


Gastrointestinal

Including having a high expression in
enterocyte Enterocytes, or intestinal absorptive cells, are simple columnar epithelial cells which line the inner surface of the small and large intestines. A glycocalyx surface coat contains digestive enzymes. Microvilli on the apical surface increase its ...
s, SGK1 is highly expressed in the
gastrointestinal tract The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organ (biology), organs of the digestive syste ...
. It has been suggested that glucocorticoids are the primary stimulant of intestinal SGK1 expression. Unlike in
renal function Assessment of kidney function occurs in different ways, using the presence of symptoms and signs, as well as measurements using urine tests, blood tests, and medical imaging. Functions of a healthy kidney include maintaining a person's fluid ...
,
ENaC The epithelial sodium channel (ENaC), (also known as amiloride-sensitive sodium channel) is a membrane-bound ion channel that is selectively permeable to sodium ions (). It is assembled as a heterotrimer composed of three homologous subunits α ...
regulation in the colon is currently not fully understood. At the current time, it seems SGK1 is not required for stimulation of ENaC in the distal colon.


Cardiovascular

The heart is one of the many tissues with high SGK1 expression. As SGK1 affects both Na+ intake and renal+ excretion, the regulation of
blood pressure Blood pressure (BP) is the pressure of circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term "blood pressure" r ...
could be influenced by SGK1-induced salt imbalance. Activated SGK1, due to
insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism o ...
, may lead to Na+ reabsorption and consequently blood pressure. SGK1 has been shown to impact the
QT interval The QT interval is a measurement made on an electrocardiogram used to assess some of the electrical properties of the heart. It is calculated as the time from the start of the Q wave to the end of the T wave, and approximates to the time taken ...
of the heart electrical cycle. As the QT interval represents the electrical depolarization and repolarization of the left and right ventricles, "SGK1 may have the capacity to shorten Q-T". "In support of this, a gene variant of SGK1, presumably conferring enhanced SGK1 activity is indeed associated with a shortened Q-T interval in humans".


Clinical significance

A gain-of-function mutation i
SGK1
or serum and glucocorticoid-inducible kinase 1, can lead to a shortening of the QT interval, which represents the repolarization time of the cardiac cells after a cardiac muscle contraction action potential. SGK1 does this by interacting with the
KvLQT1 Kv7.1 (KvLQT1) is a potassium channel protein whose primary subunit in humans is encoded by the ''KCNQ1'' gene. Kv7.1 is a voltage and lipid-gated potassium channel present in the cell membranes of cardiac tissue and in inner ear neurons among ...
channel in cardiac cells, stimulating this channel when it is complex with
KCNE1 Potassium voltage-gated channel subfamily E member 1 is a protein that in humans is encoded by the ''KCNE1'' gene. Voltage-gated potassium channels (Kv) represent the most complex class of voltage-gated ion channels from both functional and struc ...
. SGK1 stimulates the slow delayed rectifier potassium current through this channel by
phosphorylating In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, whi ...
PIKfyve, which then makes PI(3,5)P2, which goes on to increase the RAB11-dependent insertion of the KvLQT1/KCNE1 channels into the
plasma membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (t ...
of cardiac neurons. SGK1 phosphorylates PIKfyve, which results in regulated channel activity through RAB11-dependent
exocytosis Exocytosis () is a form of active transport and bulk transport in which a cell transports molecules (e.g., neurotransmitters and proteins) out of the cell ('' exo-'' + ''cytosis''). As an active transport mechanism, exocytosis requires the use o ...
of these KvLQT1/KCNE1-containing vesicles. Stress-induced stimuli have been known to activate SGK1, which demonstrates how
Long QT Syndrome Long QT syndrome (LQTS) is a condition affecting repolarization (relaxing) of the heart after a heartbeat, giving rise to an abnormally lengthy QT interval. It results in an increased risk of an irregular heartbeat which can result in fainting, d ...
is brought on by stressors to the body or to the heart itself. By increasing the insertion of KVLQT1/KCNE1 channels into the plasma membrane through an alteration of trafficking within the cell, SGK1 is able to enhance the slow delayed potassium rectifier current in the neurons.


Role in neuronal disease

Two majors components of SGK1 expression,
oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily Detoxification, detoxify the reactive intermediates or to repair the resulting damage. Disturbances ...
and an increase in glucocorticoids, are common components of the
neurodegenerative A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic ...
process. "Studies suggest that SGK1 is an important player in cell death processes underlying neurodegerative diseases, and its role seems to be neuroprotective".
AMPA α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, better known as AMPA, is a compound that is a specific agonist for the AMPA receptor, where it mimics the effects of the neurotransmitter glutamate. There are several types of glutamatergic ...
and
Kainate receptor Kainate receptors, or kainic acid receptors (KARs), are ionotropic receptors that respond to the neurotransmitter glutamate. They were first identified as a distinct receptor type through their selective activation by the agonist kainate, a drug ...
s are regulated by SGK isoforms. AMPA receptor activation is key for ischemic-induced cell death. Where changes in GluR2 levels are observed, "it has been suggested that disturbed SGK1-dependent regulation of AMPA and kainate receptors could participate in the pathophysiology of
Amyotrophic lateral sclerosis Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or Lou Gehrig's disease, is a neurodegenerative disease that results in the progressive loss of motor neurons that control voluntary muscles. ALS is the most comm ...
(ALS),
schizophrenia Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social withdra ...
, and
epilepsy Epilepsy is a group of non-communicable neurological disorders characterized by recurrent epileptic seizures. Epileptic seizures can vary from brief and nearly undetectable periods to long periods of vigorous shaking due to abnormal electrical ...
". Kainate receptors are thought to be involved in epileptic activity. Glutamate transporters act to remove glutamate from
extracellular space Extracellular space refers to the part of a multicellular organism outside the cells, usually taken to be outside the plasma membranes, and occupied by fluid. This is distinguished from intracellular space, which is inside the cells. The compositi ...
. A lack of SGK1 may prevent glutamate activity while at the same time decreasing glutamate clearance from the
synaptic cleft Chemical synapses are biological junctions through which neurons' signals can be sent to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous syste ...
. "As glutamate may exert neurotoxic effects, altered function or regulation of glutamate transporters and glutamate receptors may foster neuroexcitotoxicity".


Huntingtin

Counteracting
huntingtin Huntingtin (Htt) is the protein coded for in humans by the ''HTT'' gene, also known as the ''IT15'' ("interesting transcript 15") gene. Mutated ''HTT'' is the cause of Huntington's disease (HD), and has been investigated for this role and also for ...
toxicity, SGK1 has been found to phosphorylate huntingtin. "Genomic upregulation of SGK1 coincides with the onset of
dopaminergic Dopaminergic means "related to dopamine" (literally, "working on dopamine"), dopamine being a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain. Dopaminergic brain pathways facilitate d ...
cell death in a model of
Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
". However, at the current time, it is unclear whether SGK1 prevents or motivates cell death. An excessive expression of SGK1 has also been observed in
Rett syndrome Rett syndrome (RTT) is a genetic disorder that typically becomes apparent after 6–18 months of age and almost exclusively in females. Symptoms include impairments in language and coordination, and repetitive movements. Those affected often h ...
(RTT), which is a disorder of severe mental retardation. SGK1 is suggested to take part in the signaling of
brain-derived neurotrophic factor Brain-derived neurotrophic factor (BDNF), or abrineurin, is a protein found in the and the periphery. that, in humans, is encoded by the ''BDNF'' gene. BDNF is a member of the neurotrophin family of growth factors, which are related to the cano ...
(BDNF). It is known that BDNF is involved in neuronal survival,
plasticity Plasticity may refer to: Science * Plasticity (physics), in engineering and physics, the propensity of a solid material to undergo permanent deformation under load * Neuroplasticity, in neuroscience, how entire brain structures, and the brain it ...
, mood, and
long-term memory Long-term memory (LTM) is the stage of the Atkinson–Shiffrin memory model in which informative knowledge is held indefinitely. It is defined in contrast to short-term and working memory, which persist for only about 18 to 30 seconds. Long-t ...
. "SGK1 could participate in the signaling of BDNF during
schizophrenia Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social withdra ...
, depression, and
Alzheimer's disease Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
". "Moreover, BDNF concentrations are modified after major psychiatric treatment strategies", including
antidepressant Antidepressants are a class of medication used to treat major depressive disorder, anxiety disorders, chronic pain conditions, and to help manage addictions. Common side-effects of antidepressants include dry mouth, weight gain, dizziness, hea ...
s and
electroconvulsive therapy Electroconvulsive therapy (ECT) is a psychiatry, psychiatric treatment where a generalized seizure (without muscular convulsions) is electrically induced to manage refractory mental disorders.Rudorfer, MV, Henry, ME, Sackeim, HA (2003)"Electroco ...
.


Other neuronal diseases

*Tau protein:
Tau protein The tau proteins (abbreviated from tubulin associated unit) are a group of six highly soluble protein isoforms produced by alternative splicing from the gene ''MAPT'' (microtubule-associated protein tau). They have roles primarily in maintaining ...
is phosphorylated by SGK1. SGK1 may contribute to
Alzheimer's disease Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
, as it is paralleled by hyperphosphorylation of tau. *CreaT: "The ability of SGK1 to upregulate the creatine transporter CreaT may similarly be of pathological significance, as individuals with defective CreaT have been shown to suffer from mental retardation". *SKG1 mRNA: As SGK1 deficiency is simultaneously paired with insufficient glucocorticoid signaling, it has been suggested that it may participate in
major depressive disorder Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive low mood, low self-esteem, and loss of interest or pleasure in normally enjoyable activities. Introdu ...
. "A study looking at SGK1 mRNA expression in depressed patients found that depressed patients had significantly higher SGK1 mRNA levels".


Interactions

SGK has been shown to
interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with: *
KPNA2 Importin subunit alpha-1 is a protein that in humans is encoded by the ''KPNA2'' gene. The import of proteins into the nucleus is a process that involves at least 2 steps. The first is an energy-independent docking of the protein to the nuclear ...
, *
MAPK7 Mitogen-activated protein kinase 7 also known as MAP kinase 7 is an enzyme that in humans is encoded by the ''MAPK7'' gene. Function MAPK7 is a member of the MAP kinase family. MAP kinases act as an integration point for multiple biochemical ...
, *
NEDD4 E3 ubiquitin-protein ligase NEDD4, also known as neural precursor cell expressed developmentally down-regulated protein 4 (whence "NEDD4") is an enzyme that is, in humans, encoded by the ''NEDD4'' gene. NEDD4 is an E3 ubiquitin ligase enzyme, that ...
, *
PDPK1 In the field of biochemistry, PDPK1 refers to the protein 3-phosphoinositide-dependent protein kinase-1, an enzyme which is encoded by the ''PDPK1'' gene in humans. It is implicated in the development and progression of melanomas. Function PD ...
, and * SLC9A3R2.


References


External links

* {{PDBe-KB2, O00141, Serine/threonine-protein kinase Sgk1 Molecular neuroscience