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 residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
encoded, in humans, by the ''SLC2A4''
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 ...
. 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 anabolic hormone of the body. It regulates the metabolism o ...
-regulated
glucose transporter
Glucose transporters are a wide group of membrane proteins that facilitate the transport of glucose across the plasma membrane, a process known as facilitated diffusion. Because glucose is a vital source of energy for all life, these transporter ...
found primarily in
adipose tissues and
striated muscle (skeletal and cardiac). The first evidence for this distinct glucose transport protein was provided by
David James Dewi, Dai, Dafydd or David James may refer to:
Performers
*David James (actor, born 1839) (1839–1893), English stage comic and a founder of London's Vaudeville Theatre
*David James (actor, born 1967) (born 1967), Australian presenter of ABC's ''P ...
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 cells in the liver and pancreas of humans and most other vertebrates. In each of these organs it plays an important role in ...
in the liver and
hexokinase
A hexokinase is an enzyme that phosphorylates hexoses (six-carbon sugars), forming hexose phosphate. In most organisms, glucose is the most important substrate for hexokinases, and glucose-6-phosphate is the most important product. Hexokina ...
in other tissues to form
glucose-6-phosphate
Glucose 6-phosphate (G6P, sometimes called the Robison ester) is a glucose sugar phosphorylated at the hydroxy group on carbon 6. This dianion is very common in cells as the majority of glucose entering a cell will become phosphorylated in this wa ...
, which then enters
glycolysis
Glycolysis is the metabolic pathway that converts glucose () into pyruvate (). The free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH ...
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
![PDB 2al3 EBI](https://upload.wikimedia.org/wikipedia/commons/c/cb/PDB_2al3_EBI.jpg)
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 sc ...
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 formula . It can be viewed as a benzyl group substituted for the methyl group of alanine, or a phenyl group in place of a terminal hydrogen of alanine. This essential amino a ...
on the N-terminus, two
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, which then buds off inside the cell to form a vesicle containing the ingested material. E ...
and
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 ...
.
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 objects in which repetitions are allowed and order matters. Like a set, it contains members (also called ''elements'', or ''terms''). The number of elements (possibly infinite) is calle ...
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 eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. The ...
of the cell, and they all have 12 transmembrane segments.
Tissue distribution
Skeletal muscle
![1008 Skeletal Muscle Contraction](https://upload.wikimedia.org/wikipedia/commons/2/24/1008_Skeletal_Muscle_Contraction.jpg)
In striated
skeletal muscle
Skeletal muscles (commonly referred to as muscles) are 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 types of muscl ...
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 may refer to:
Companies and organizations
* Association of Tennis Professionals, men's professional tennis governing body
* American Technical Publishers, employee-owned publishing company
* ', a Danish pension
* Armenia Tree Project, non ...
to be used as energy. As
G-6-P concentrations decrease,
hexokinase
A hexokinase is an enzyme that phosphorylates hexoses (six-carbon sugars), forming hexose phosphate. In most organisms, glucose is the most important substrate for hexokinases, and glucose-6-phosphate is the most important product. Hexokina ...
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
Facilitated diffusion (also known as facilitated transport or passive-mediated transport) is the process of spontaneous passive transport (as opposed to active transport) of molecules or ions across a biological membrane via specific transmembra ...
.
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 tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle th ...
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 or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, fr ...
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 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, commonly known as fat, is a depository for energy in order to conserve metabolic
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 ...
. 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 o ...
(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 and
hyperplasia
Hyperplasia (from ancient Greek ὑπέρ ''huper'' 'over' + πλάσις ''plasis'' 'formation'), or hypergenesis, is an enlargement of an organ or tissue caused by an increase in the amount of organic tissue that results from cell proliferati ...
, which lead to obesity.
In addition, mutations in GLUT4 genes in
adipocyte
Adipocytes, also known as lipocytes and fat cells, are the 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 adipogenesis. I ...
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 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
In cell biology, a vesicle is a structure within or outside a cell, consisting of liquid or cytoplasm enclosed by a lipid bilayer. Vesicles form naturally during the processes of secretion ( exocytosis), uptake ( endocytosis) and transport of ma ...
, and is quickly incorporated into the plasma membrane of the cell when insulin binds to
membrane receptors
A membrane is a selective barrier; it allows some things to pass through but stops others. Such things may be molecules, ions, or other small particles. Membranes can be generally classified into synthetic membranes and biological membranes. B ...
.
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.
![Signal_Transduction_Diagram-_Insulin](https://upload.wikimedia.org/wikipedia/commons/4/4f/Signal_Transduction_Diagram-_Insulin.svg)
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
* Bioc ...
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 electr ...
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 homeo ...
in its
dimeric form and activates the receptor's tyrosine-kinase domain. The receptor then recruits Insulin Receptor Substrate, or
IRS-1
Insulin receptor substrate 1 (IRS-1) is a signaling adapter protein that in humans is encoded by the ''IRS-1'' gene. It is a 131 kDa protein with amino acid sequence of 1242 residues. It contains a single pleckstrin homology (PH) domain at the N-te ...
, which binds the enzyme PI-3 kinase. PI-3 kinase converts the membrane lipid
PIP2
Phosphatidylinositol 4,5-bisphosphate or PtdIns(4,5)''P''2, also known simply as PIP2 or PI(4,5)P2, is a minor phospholipid component of cell membranes. PtdIns(4,5)''P''2 is enriched at the plasma membrane where it is a substrate for a number of ...
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
AS160 (Akt substrate of 160 kDa), which was originally known as TBC1 domain family member 4 (TBC1D4), is a Rab GTPase-activating protein that in humans is encoded by the ''TBC1D4'' gene.
The 160 kD protein product was first discovered in a scree ...
, 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 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 "knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are importan ...
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 by replacing it or disrupting it with an artificial piece of DNA. They are importan ...
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 increased ap ...
.
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.
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
Death-associated protein 6 also known as Daxx is a protein that in humans is encoded by the ''DAXX'' gene.
Function
Daxx, a Death domain-associated protein, was first discovered through its cytoplasmic interaction with the classical death rece ...
, also known as Daxx. Daxx, which is used to regulate
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 ...
, 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 Greek , 'seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, a ...
. 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.
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Solute carrier family