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 transmembra ...

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) o ...

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 mem ...

and symporters. 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 signif ...

known as transporters that move molecules 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 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

and symporters. 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 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 ...

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 m ...

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 chemica ...

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. Crane, 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. Hexok ...

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 phosph ...

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 changes 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 "bless ...

in 1966. This cycle of conformational changes only transports one substrate ion at a time, which results in a fairly slow transport rate (10⁰ to 10⁴ ions or molecules per second) when compared to other transport proteins like ion channels. 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 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 conve ...

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 a one-to-one ratio across the plasma membrane based only on the

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 trans ...

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 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 atmosph ...

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 sa ...

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.

References

{{Reflist Integral membrane proteins Transport phenomena pl:Symport