GLUT4
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Glucose transporter type 4 (GLUT4), also known as solute carrier family 2, facilitated glucose transporter member 4, is a
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metabo ...

protein
encoded, in humans, by the ''SLC2A4''
gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian inheritance#History, Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanin ...

gene
. GLUT4 is the
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 Anabolism, anabolic hormone of the body. It regulates the m ...

insulin
-regulated glucose transporter found primarily in
adipose Adipose tissue, body fat, or simply fat is a loose connective tissue Connective tissue is one of the four primary types of animal tissue (biology), tissue, along with epithelial tissue, muscle tissue, and nervous tissue. It develops from the ...
tissues and
striated muscle Striations means a series of ridges, furrows or linear marks, and is used in several ways: * Glacial striation * Striation (fatigue), in material * Striation (geology), a ''striation'' as a result of a geological Fault (geology), fault * Striation ...

striated muscle
(skeletal and cardiac). The first evidence for this distinct glucose transport protein was provided by David James in 1988. The gene that encodes GLUT4 was cloned and mapped in 1989. At the cell surface, GLUT4 permits the facilitated diffusion of circulating glucose down its concentration gradient into muscle and fat cells. Once within cells, glucose is rapidly phosphorylated by
glucokinase Glucokinase () is an enzyme that facilitates phosphorylation of glucose to glucose-6-phosphate. Glucokinase occurs in cell (biology), cells in the liver and pancreas of humans and most other vertebrates. In each of these organs it plays an imp ...

glucokinase
in the liver and
hexokinase A hexokinase is an enzyme that phosphorylation, phosphorylates hexoses (six-carbon sugars), forming hexose phosphate. In most organisms, glucose is the most important substrate (biochemistry), substrate for hexokinases, and glucose-6-phospha ...
in other tissues to form glucose-6-phosphate, which then enters
glycolysis Glycolysis is the metabolic pathway that converts glucose () into pyruvic acid, pyruvate (). The Thermodynamic free energy, free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and NADH, red ...

glycolysis
or is polymerized into glycogen. Glucose-6-phosphate cannot diffuse back out of cells, which also serves to maintain the concentration gradient for glucose to passively enter cells.


Structure

Like all proteins, the unique amino acid arrangement in the
primary sequence Biomolecular structure is the intricate folded, three-dimensional shape that is formed by a molecule of protein, DNA, or RNA, and that is important to its function. The structure of these molecules may be considered at any of several length sca ...
of GLUT4 is what allows it to transport glucose across the plasma membrane. In addition to the
phenylalanine Phenylalanine (symbol Phe or F) is an essential α-amino acid with the chemical formula, formula . It can be viewed as a benzyl group substituent, substituted for the methyl group of alanine, or a phenyl group in place of a terminal hydrogen of al ...

phenylalanine
on the N-terminus, two
Leucine Leucine (symbol Leu or L) is an essential amino acid that is used in the biosynthesis of proteins. Leucine is an α-amino acid, meaning it contains an α-amino group (which is in the protonated −NH3+ form under biological conditions), an α-Car ...

Leucine
residues and acidic motifs on the COOH-terminus are believed to play a key role in the kinetics of
endocytosis Endocytosis is a cellular process in which substances are brought into the cell. The material to be internalized is surrounded by an area of cell membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, an ...

endocytosis
and
exocytosis Exocytosis () is a form of active transport and solvent drag, bulk transport in which a cell transports molecules (e.g., neurotransmitters and proteins) out of the cell (''wikt:ex-#Prefix, exo-'' + ''cytosis''). As an active transport mechanism, ...
.


Other GLUT proteins

There are 14 total GLUT proteins separated into 3 classes based on
sequence In mathematics, a sequence is an enumerated collection of mathematical object, objects in which repetitions are allowed and order theory, order matters. Like a Set (mathematics), set, it contains Element (mathematics), members (also called ''eleme ...

sequence
similarities. Class 1 consists of GLUT 1-4 and 14, class 2 contains GLUT 5, 7, 9 and 11, and class 3 has GLUT 6, 8, 10, 12 and 13. Although there are some sequence differences between all GLUT proteins, they all have some basic structural components. For example, both the N and C termini in GLUT proteins are exposed to the
cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryote, eukaryotic Cell (biology), cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear envelope, nuc ...
of the cell, and they all have 12 transmembrane segments.


Tissue distribution


Skeletal muscle

In striated
skeletal muscle Skeletal muscles (commonly referred to as muscles) are Organ (biology), organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other ...

skeletal muscle
cells, GLUT4 concentration in the plasma membrane can increase as a result of either exercise or muscle contraction. During exercise, the body needs to convert glucose to
ATP
ATP
to be used as energy. As G-6-P concentrations decrease,
hexokinase A hexokinase is an enzyme that phosphorylation, phosphorylates hexoses (six-carbon sugars), forming hexose phosphate. In most organisms, glucose is the most important substrate (biochemistry), substrate for hexokinases, and glucose-6-phospha ...
becomes less inhibited, and the glycolytic and oxidative pathways that make ATP are able to proceed. This also means that muscle cells are able to take in more glucose as its intracellular concentrations decrease. In order to increase glucose levels in the cell, GLUT4 is the primary transporter used in this facilitated diffusion. Although muscle contractions function in a similar way and also induce the translocation of GLUT4 into the plasma membrane, the two skeletal muscle processes obtain different forms of intracellular GLUT4. The GLUT4 carrier vesicles are either transferrin positive or negative, and are recruited by different stimuli. Transferrin-positive GLUT4 vesicles are utilized during muscle contraction while the transferrin-negative vesicles are activated by insulin stimulation as well as by exercise.


Cardiac muscle

Cardiac muscle Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate Muscle tissue, muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striat ...

Cardiac muscle
is slightly different from skeletal muscle. At rest, they prefer to utilize
fatty acid In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated and unsaturated compounds#Organic chemistry, saturated or unsaturated. Most naturally occurring fatty acids have an B ...
s as their main energy source. As activity increases and it begins to pump faster, the cardiac muscles begin to oxidize glucose at a higher rate.  An analysis of mRNA levels of
GLUT1 Glucose transporter 1 (or GLUT1), also known as solute carrier family 2, facilitated glucose transporter member 1 (SLC2A1), is a uniporter A uniporter is a membrane transport protein that transports a single species of Substrate (biochemistry) ...
and GLUT4 in cardiac muscles show that GLUT1 plays a larger role in cardiac muscles than it does in skeletal muscles. GLUT4, however, is still believed to be the primary transporter for glucose. Much like in other tissues, GLUT4 also responds to insulin signaling, and is transported into the plasma membrane to facilitate the diffusion of glucose into the cell. 


Adipose tissue

Adipose tissue Adipose tissue, body fat, or simply fat is a loose connective tissue composed mostly of adipocytes. In addition to adipocytes, adipose tissue contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular en ...

Adipose tissue
, commonly known as fat, is a depository for energy in order to conserve metabolic
homeostasis In biology, homeostasis ( British also homoeostasis) (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physical, and chemical conditions maintained by living systems. This is the condition of optimal functioning for the organism ...
. As the body takes in energy in the form of glucose, some is expended, and the rest is stored as
glycogen Glycogen is a multibranched polysaccharide of glucose that serves as a form of energy storage in animals, fungi, and bacteria. The polysaccharide structure represents the main storage form of glucose in the body. Glycogen functions as one of ...

glycogen
(primarily in the liver, muscle cells), or as triglyceride in adipose tissue. An imbalance in glucose intake and energy expenditure has been shown to lead to both adipose cell
hypertrophy Hypertrophy is the increase in the volume of an organ or tissue due to the enlargement of its component Cell (biology), cells. It is distinguished from hyperplasia, in which the cells remain approximately the same size but increase in number.Upda ...

hypertrophy
and hyperplasia, which lead to obesity. In addition, mutations in GLUT4 genes in
adipocyte Adipocytes, also known as lipocytes and fat cells, are the cell (biology), cells that primarily compose adipose tissue, specialized in storing energy as fat. Adipocytes are derived from mesenchymal stem cells which give rise to adipocytes through ...

adipocyte
s can also lead to increased GLUT4 expression in adipose cells, which allows for increased glucose uptake and therefore more fat stored. If GLUT4 is over-expressed, it can actually alter nutrient distribution and send excess glucose into adipose tissue, leading to increased adipose tissue mass. 


Regulation


Insulin

Insulin is released from the pancreas and into the bloodstream in response to increased glucose concentration in the blood. Insulin is stored in
beta cells Beta cells (β-cells) are a type of cell (biology), cell found in pancreatic islets that synthesize and secrete insulin and amylin. Beta cells make up 50–70% of the cells in human islets. In patients with Type 1 diabetes, beta-cell mass and fun ...
in the pancreas. When glucose in the blood binds to glucose receptors on the beta cell membrane, a signal cascade is initiated inside the cell that results in insulin stored in
vesicle Vesicle may refer to: ; In cellular biology or chemistry * Vesicle (biology and chemistry), a supramolecular assembly of lipid molecules, like a cell membrane * Synaptic vesicle ; In human embryology * Vesicle (embryology), bulge-like features o ...
s in these cells being released into the blood stream. Increased insulin levels cause the uptake of glucose into the cells. GLUT4 is stored in the cell in transport vesicles, and is quickly incorporated into the plasma membrane of the cell when insulin binds to membrane receptors. Under conditions of low insulin, most GLUT4 is sequestered in intracellular vesicles in muscle and fat cells. As the vesicles fuse with the plasma membrane, GLUT4 transporters are inserted and become available for transporting glucose, and glucose absorption increases. The genetically engineered muscle insulin receptor knock‐out (MIRKO) mouse was designed to be insensitive to glucose uptake caused by insulin, meaning that GLUT4 is absent. Mice with diabetes or fasting hyperglycemia, however, were found to be immune to the negative effects of the insensitivity. The mechanism for GLUT4 is an example of a
cascade Cascade, Cascades or Cascading may refer to: Science and technology Science *Cascade waterfalls, or series of waterfalls * Cascade, the CRISPR-associated complex for antiviral defense (a protein complex) * Cascade (grape), a type of fruit * Bioch ...

cascade
effect, where binding of a
ligand In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electro ...
to a membrane receptor amplifies the signal and causes a cellular response. In this case, insulin binds to the
insulin receptor The insulin receptor (IR) is a transmembrane receptor that is activated by insulin, IGF-I, IGF-II and belongs to the large class of receptor tyrosine kinase. Metabolically, the insulin receptor plays a key role in the regulation of glucose ...

insulin receptor
in its dimeric form and activates the receptor's tyrosine-kinase domain. The receptor then recruits Insulin Receptor Substrate, or IRS-1, which binds the enzyme PI-3 kinase. PI-3 kinase converts the membrane lipid to PIP3. PIP3 is specifically recognized by PKB (
protein kinase B Protein kinase B (PKB), also known as Akt, is the collective name of a set of three serine/threonine-specific protein kinases that play key roles in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, transc ...
) and by PDK1, which can phosphorylate and activate PKB. Once phosphorylated, PKB is in its active form and phosphorylates TBC1D4, which inhibits the GTPase-activating domain associated with TBC1D4, allowing for Rab protein to change from its GDP to GTP bound state. Inhibition of the GTPase-activating domain leaves proteins next in the cascade in their active form, and stimulates GLUT4 to be expressed on the plasma membrane. RAC1 is a
GTPase GTPases are a large family of hydrolase enzymes that bind to the nucleotide Guanosine triphosphate, guanosine triphosphate (GTP) and hydrolysis, hydrolyze it to Guanosine diphosphate, guanosine diphosphate (GDP). The GTP binding and hydrolysis take ...
also activated by insulin. Rac1 stimulates reorganization of the cortical Actin cytoskeleton which allows for the GLUT4 vesicles to be inserted into the plasma membrane. A RAC1
Knockout mouse A knockout mouse, or knock-out mouse, is a genetically modified mouse (''Mus musculus'') in which researchers have inactivated, or "Gene knockout, knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They ...
has reduced glucose uptake in muscle tissue.
Knockout mice A knockout mouse, or knock-out mouse, is a genetically modified mouse (''Mus musculus'') in which researchers have inactivated, or " knocked out", an existing gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word ge ...
that are heterozygous for GLUT4 develop
insulin resistance Insulin resistance (IR) is a pathological condition in which cell (biology), cells fail to respond normally to the hormone insulin. Insulin is a hormone that facilitates the transport of glucose from blood into cells, thereby reducing blood gluco ...
in their muscles as well as
diabetes Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increase ...

diabetes
.


Muscle contraction

Muscle contraction stimulates muscle cells to translocate GLUT4 receptors to their surfaces. This is especially true in cardiac muscle, where continuous contraction increases the rate of GLUT4 translocation; but is observed to a lesser extent in increased skeletal muscle contraction. In skeletal muscle, muscle contractions increase GLUT4 translocation several fold, and this is likely regulated by RAC1 and
AMP-activated protein kinase 5' AMP-activated protein kinase or AMPK or 5' adenosine monophosphate-activated protein kinase is an enzyme (EC 2.7.11.31) that plays a role in cellular energy homeostasis, largely to activate glucose and fatty acid uptake and oxidation when cell ...
.


Muscle stretching

Muscle stretching also stimulates GLUT4 translocation and glucose uptake in rodent muscle via RAC1.


Interactions

GLUT4 has been shown to interact with death-associated protein 6, also known as Daxx. Daxx, which is used to regulate
apoptosis Apoptosis (from grc, wikt:ἀπόπτωσις, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemistry, Biochemical events lead to characteristic cell changes (Morp ...

apoptosis
, has been shown to associate with GLUT4 in the cytoplasm. UBX-domains, such as the one found in GLUT4, have been shown to associate with apoptotic signaling. So this interaction aids in the translocation of Daxx within the cell. In addition, recent reports demonstrated the presence of GLUT4 gene in central nervous system such as the
hippocampus The hippocampus (via Latin from Ancient Greek, Greek , 'seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each cerebral hemisphere, side of the brain. The hippocamp ...

hippocampus
. Moreover, impairment in insulin-stimulated trafficking of GLUT4 in the hippocampus result in decreased metabolic activities and plasticity of hippocampal neurons, which leads to depressive like behaviour and cognitive dysfunction.


Interactive pathway map


References


External links

*
''USCD—Nature molecule pages: The signaling pathway", "GLUT4"
contains a high-resolution network map. Accessed 25 December 2009. {{Solute carrier family, bg, bg0 Solute carrier family