Cotransporters are a subcategory of
membrane transport protein
A membrane transport protein (or simply transporter) is a membrane protein involved in the movement of ions, small molecules, and macromolecules, such as another protein, across a biological membrane. Transport proteins are integral transmembran ...
s (transporters) that couple the favorable movement of one molecule with its
concentration gradient
Molecular diffusion, often simply called diffusion, is the thermal motion of all (liquid or gas) particles at temperatures above absolute zero. The rate of this movement is a function of temperature, viscosity of the fluid and the size (mass) of ...
and unfavorable movement of another molecule against its concentration gradient. They enable
coupled or cotransport (secondary active transport) and include
antiporters
An antiporter (also called exchanger or counter-transporter) is a cotransporter and integral membrane protein involved in secondary active transport of two or more different molecules or ions across a phospholipid membrane such as the plasma membr ...
and
symporters
A symporter is an integral membrane protein that is involved in the transport of two (or more) different molecules across the cell membrane in the same direction. The symporter works in the plasma membrane and molecules are transported across the ...
. In general, cotransporters consist of two out of the three classes of
integral membrane proteins
An integral, or intrinsic, membrane protein (IMP) is a type of membrane protein that is permanently attached to the biological membrane. All ''transmembrane proteins'' are IMPs, but not all IMPs are transmembrane proteins. IMPs comprise a signi ...
known as transporters that move
molecules
A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and bioche ...
and
ions
An ion () is an atom or molecule with a net electrical charge.
The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conven ...
across biomembranes.
Uniporters
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 transmembr ...
are also transporters but move only one type of molecule down its concentration gradient and are not classified as cotransporters.
Background
Cotransporters are capable of moving solutes either up or down gradients at rates of 1000 to 100000 molecules per second. They may act as channels or transporters, depending on conditions under which they are assayed. The movement occurs by binding to two molecules or ions at a time and using the gradient of one solute's concentration to force the other molecule or ion against its gradient. Some studies show that cotransporters can function as ion channels, contradicting the classical models. For instance the wheat HKT1 transporter shows two modes of transport by the same protein.
Cotransporters can be classified as
antiporters
An antiporter (also called exchanger or counter-transporter) is a cotransporter and integral membrane protein involved in secondary active transport of two or more different molecules or ions across a phospholipid membrane such as the plasma membr ...
and
symporters
A symporter is an integral membrane protein that is involved in the transport of two (or more) different molecules across the cell membrane in the same direction. The symporter works in the plasma membrane and molecules are transported across the ...
. Both use
electric potential
The electric potential (also called the ''electric field potential'', potential drop, the electrostatic potential) is defined as the amount of work energy needed to move a unit of electric charge from a reference point to the specific point in ...
and/or chemical gradients to move protons and ions against their concentration gradient. In plants the
proton
A proton is a stable subatomic particle, symbol , H+, or 1H+ with a positive electric charge of +1 ''e'' elementary charge. Its mass is slightly less than that of a neutron and 1,836 times the mass of an electron (the proton–electron mass ...
is considered a secondary substance and high proton concentration in the
apoplast
Inside a plant, the apoplast can mean the space outside of cell membranes, where material can diffuse freely; that is, the extracellular spaces.
''Apoplast '' can also refer especially to the continuum of cell walls of adjacent cells; fluid and ma ...
powers the inward movement of certain ions by symporters. A
Proton gradient
An electrochemical gradient is a gradient of electrochemical potential, usually for an ion that can move across a membrane. The gradient consists of two parts, the chemical gradient, or difference in solute concentration across a membrane, and th ...
moves the ions into the
vacuole
A vacuole () is a membrane-bound organelle which is present in plant and fungal cells and some protist, animal, and bacterial cells. Vacuoles are essentially enclosed compartments which are filled with water containing inorganic and organic mo ...
by proton-sodium antiporter or the proton-calcium antiporter. In plants, sucrose transport is distributed throughout the plant by the proton-pump where the pump, as discussed above, creates a gradient of protons so that there are many more on one side of the membrane than the other. As the protons diffuse back across the membrane, the free energy liberated by this
diffusion
Diffusion is the net movement of anything (for example, atoms, ions, molecules, energy) generally from a region of higher concentration to a region of lower concentration. Diffusion is driven by a gradient in Gibbs free energy or chemical p ...
is used to co-transport sucrose. In mammals, glucose is transported through sodium dependent glucose transporters, which use energy in this process. Here, since both glucose and sodium are transported in the same direction across the membrane, they would be classified as symporters. The glucose transporter system was first hypothesized by Dr. Robert K. Crane in 1960, this is discussed later in the article.
History
![Dr Robert K](https://upload.wikimedia.org/wikipedia/commons/4/41/Dr_Robert_K._Crane_and_his_sketch_for_coupled_cotransport.png)
Dr.
Robert K. Crane
Robert Kellogg Crane (December 20, 1919 – October 31, 2010) was an American biochemist best known for his discovery of sodium–glucose cotransport.
Biography
Crane was born on December 20, 1919 in Palmyra, New Jersey, to Wilbur Fiske Crane, J ...
, a Harvard graduate, had been working in the field of carbohydrate biochemistry for quite some time. His experience in the areas of
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 ...
biochemistry, carbon dioxide fixation,
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 ...
and
phosphate
In chemistry, a phosphate is an anion, salt, functional group or ester derived from a phosphoric acid. It most commonly means orthophosphate, a derivative of orthophosphoric acid .
The phosphate or orthophosphate ion is derived from phospho ...
studies led him to hypothesize cotransport of glucose along with sodium through the intestine. Pictured right is of Dr. Crane and his drawing of the cotransporter system he proposed in 1960, at the international meet on membrane transport and metabolism. His studies were confirmed by other groups and are now used as the classical model to understand cotransporters.
Mechanism
Antiporters and symporters both transport two or more different types of molecules at the same time in a coupled movement. An energetically unfavored movement of one molecule is combined with an energetically favorable movement of another molecule(s) or ion(s) to provide the power needed for transport. This type of transport is known as
secondary active transport
In cellular biology, ''active transport'' is the movement of molecules or ions across a cell membrane from a region of lower concentration to a region of higher concentration—against the concentration gradient. Active transport requires cellul ...
and is powered by the energy derived from the concentration gradient of the ions/molecules across the membrane the cotransporter protein is integrated within.
Cotransporters undergo a cycle of
conformational change
In biochemistry, a conformational change is a change in the shape of a macromolecule, often induced by environmental factors.
A macromolecule is usually flexible and dynamic. Its shape can change in response to changes in its environment or oth ...
s by linking the movement of an ion with its concentration gradient (downhill movement) to the movement of a cotransported solute against its concentration gradient (uphill movement).
In one conformation the protein will have the binding site (or sites in the case of symporters) exposed to one side of the membrane. Upon binding of both the molecule which is to be transported uphill and the molecule to be transported downhill a conformational change will occur. This conformational change will expose the bound substrates to the opposite side of the membrane, where the substrates will disassociate. Both the molecule and the cation must be bound in order for the conformational change to occur. This mechanism was first introduced by
Oleg Jardetzky
Oleg (russian: Олег), Oleh ( uk, Олег), or Aleh ( be, Алег) is an East Slavic given name. The name is very common in Russia, Ukraine and Belаrus. It derives from the Old Norse ''Helgi'' ( Helge), meaning "holy", "sacred", or "blesse ...
in 1966. This cycle of conformational changes only transports one substrate ion at a time, which results in a fairly slow transport rate (10
0 to 10
4 ions or molecules per second) when compared to other transport proteins like
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.
The rate at which this cycle of conformational changes occurs is called the turnover rate (TOR) and is expressed as the average number of complete cycles per second performed by a single cotransporter molecule.
Types
Antiporters
Antiporters use the mechanism of cotransport (coupling the movement of one ion or molecule down its concentration gradient with the transport of another ion or molecule up its concentration gradient), to move the ions and molecule in opposite directions.
In this situation one of the ions will move from the exoplasmic space into the
cytoplasmic space while the other ion will move from the cytoplasmic space into the exoplasmic space. An example of an antiporter is the
sodium-calcium exchanger
The sodium-calcium exchanger (often denoted Na+/Ca2+ exchanger, exchange protein, or NCX) is an antiporter membrane protein that removes calcium from cells. It uses the energy that is stored in the electrochemical gradient of sodium (Na+) by al ...
. The sodium-calcium exchanger functions to remove excess calcium from the cytoplasmic space into the exoplasmic space against its concentration gradient by coupling its transport with the transport of sodium from the exoplasmic space down its concentration gradient (established by the
active transport
In cellular biology, ''active transport'' is the movement of molecules or ions across a cell membrane from a region of lower concentration to a region of higher concentration—against the concentration gradient. Active transport requires cellul ...
of sodium out of the cell by the
sodium-potassium pump) into the cytoplasmic space. The sodium-calcium exchanger exchanges 3 sodium ions for 1 calcium ion and represents a
cation
An ion () is an atom or molecule with a net electrical charge.
The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by convent ...
antiporter.
Cells also contain
anion
An ion () is an atom or molecule with a net electrical charge.
The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by convent ...
antiporters such as the
Band 3
Band 3 anion transport protein, also known as anion exchanger 1 (AE1) or band 3 or solute carrier family 4 member 1 (SLC4A1), is a protein that is encoded by the gene in humans.
Band 3 anion transport protein is a phylogenetically-preserved ...
(or AE1) anion transport protein. This cotransporter is an important integral protein in mammalian
erythrocytes
Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...
and moves
chloride ion
The chloride ion is the anion (negatively charged ion) Cl−. It is formed when the element chlorine (a halogen) gains an electron or when a compound such as hydrogen chloride is dissolved in water or other polar solvents. Chloride salts ...
and
bicarbonate ion
In inorganic chemistry, bicarbonate (IUPAC-recommended nomenclature: hydrogencarbonate) is an intermediate form in the deprotonation of carbonic acid. It is a polyatomic anion with the chemical formula .
Bicarbonate serves a crucial biochemica ...
in a one-to-one ratio across the plasma membrane based only on the
concentration gradient
Molecular diffusion, often simply called diffusion, is the thermal motion of all (liquid or gas) particles at temperatures above absolute zero. The rate of this movement is a function of temperature, viscosity of the fluid and the size (mass) of ...
of the two ions. The AE1 antiporter is essential in the removal of
carbon dioxide
Carbon dioxide (chemical formula ) is a chemical compound made up of molecules that each have one carbon atom covalently double bonded to two oxygen atoms. It is found in the gas state at room temperature. In the air, carbon dioxide is transpar ...
waste that is converted to bicarbonate inside the erythrocyte.
Symporters
In contrast to antiporters, symporters move ions or molecules in the same direction.
In this case both ions being transported will be moved either from the exoplasmic space into the cytoplasmic space or from the cytoplasmic space into the exoplasmic space. An example of a symporter is the
sodium-glucose linked transporter or SGLT. The SGLT functions to couple the transport of sodium in the exoplasmic space down its concentration gradient (again, established by the active transport of sodium out of the cell by the
sodium-potassium pump) into the cytoplasmic space to the transport of glucose in the exoplasmic space against its concentration gradient into the cytoplasmic space. The SGLT couples the movement of 1 glucose ion with the movement of 2 sodium ions.
Examples of cotransporters
Na+/glucose cotransporter (SGLT1) – is also known as sodium-glucose cotransporter 1 and is encoded by the SLC5A1 gene. SGLT1 is an electrogenic transporter as the sodium electrochemical gradient drives glucose uphill into the cells. SGLT1 is a high affinity Na
+ /glucose cotransporter that has an important role in transferring sugar across the epithelial cells of renal proximal tubules and of the intestine, in particular the small intestine.
Na+/phosphate cotransporter (NaPi) – Sodium-phosphate cotransporters are from the SLC34 and SLC20 protein families. They are also found across the epithelial cells of renal proximal tubule and of the small intestine. It transfers inorganic phosphate into cells through active transport with the help of a Na
+ gradient. Similar to SGTL1, they are classified as electrogenic transporters. NaPi coupled with 3 Na
+ ions and 1 divalent Pi, are classified as NaPi IIa and NaPi IIb. NaPi that couples with 2 Na
+ and 1 divalent Pi are classified as NaPi IIc.
Na+/I− symporter (NIS) – Sodium-Iodide is a type of symporter that is responsible for transferring iodide in the thyroid gland. NIS is primarily found in cells of the thyroid gland and also in the mammary glands. They are located on the basolateral membrane of thyroid follicular cells where 2 Na
+ ions and 1 I
− ion is coupled to transfer the iodide. NIS activity helps in the diagnosis and treatment of thyroid disease, including the highly successful treatment of thyroid cancer with radioiodide after thyroidectomy.
Na-K-2Cl symporter
The Na-K-Cl cotransporter (NKCC) is a protein that aids in the secondary active transport of sodium, potassium, and chloride into cells. In humans there are two isoforms of this membrane transport protein, NKCC1 and NKCC2, encoded by two differ ...
– This specific cotransporter regulates the cell volume by controlling the water and
electrolyte
An electrolyte is a medium containing ions that is electrically conducting through the movement of those ions, but not conducting electrons. This includes most soluble salts, acids, and bases dissolved in a polar solvent, such as water. Upon dis ...
content within the cell.
The Na-K-2Cl Cotransporter is vital in salt secretion in secretory epithelia cells along with renal salt reabsorption.
Two variations of the Na-K-2Cl symporter exist and are known as NKCC1 and NKCC2. The NKCC1 cotransport protein is found throughout the body but NKCC2 is found only in the kidney and removes the sodium, potassium, and chloride found in the body's urine, so it can be absorbed into the blood.
GABA transporter (GAT) – neurotransmitter γ-aminobutyric acid (GABA) transporters are members of the solute carrier family 6 (SLC6) of sodium- and chloride-dependent neurotransmitter receptor transporters that are located in the plasma membrane and regulate the concentration of GABA in 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 ...
. The SLC6A1 gene encodes GABA transporters.
The transporters are electrogenic and couples 2 Na
+, 1 Cl
− and 1 GABA for inward translocation.
K+Cl− Symporter – The K
+-Cl
− cotransporter family consists of four specific symporters known as KCC1, KCC2, KCC3, and KCC4. The KCC2 isoform is specific to
neuronal
A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. No ...
tissue and the other three can be found in various tissues throughout the body. This cotransporter family controls the concentration levels of
potassium
Potassium is the chemical element with the symbol K (from Neo-Latin ''kalium'') and atomic number19. Potassium is a silvery-white metal that is soft enough to be cut with a knife with little force. Potassium metal reacts rapidly with atmosphe ...
and
chloride
The chloride ion is the anion (negatively charged ion) Cl−. It is formed when the element chlorine (a halogen) gains an electron or when a compound such as hydrogen chloride is dissolved in water or other polar solvents. Chloride salts ...
within cells through the combined movement of K
+/H
+ and Cl
−/HCO3
− exchangers or through combined movement of both ions due to concentration activated channels. The four known KCC proteins team up to form two separate subfamilies with KCC1 and KCC3 pairing together and KCC2 and KCC4 becoming a pair to facilitate ion movement.
Associated diseases
Table 1: List of diseases related to transporters.
See also
*
Na-K-2Cl symporter
The Na-K-Cl cotransporter (NKCC) is a protein that aids in the secondary active transport of sodium, potassium, and chloride into cells. In humans there are two isoforms of this membrane transport protein, NKCC1 and NKCC2, encoded by two differ ...
*
K-Cl cotransporter The chloride potassium symporter is a membrane transport protein of the solute carrier family 12 that is present in the S3-segment of the renal proximal tubule Page 780 and in the neuron. It functions in renal chloride reabsorption to transport chl ...
*
Sodium/phosphate cotransporter The sodium/phosphate cotransporter is a member of the phosphate:Na+ symporter (PNaS) family within the TOG Superfamily of transport proteins as specified in the Transporter Classification Database (TCDB).
Nomenclature
Sodium/phosphate cotranspo ...
*
Sodium-glucose transport proteins
Sodium-dependent glucose cotransporters (or sodium-glucose linked transporter, SGLT) are a family of glucose transporter found in the intestinal mucosa (enterocytes) of the small intestine (SGLT1) and the proximal tubule of the nephron (SGLT2 in ...
*
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 ...
*
Cystic fibrosis
Cystic fibrosis (CF) is a rare genetic disorder that affects mostly the lungs, but also the pancreas, liver, kidneys, and intestine. Long-term issues include difficulty breathing and coughing up mucus as a result of frequent lung infections. O ...
References
{{Reflist
Integral membrane proteins
Transport phenomena
pl:Symport