Cotransporters are a subcategory of

membrane transport protein A membrane transport protein 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 membrane proteins, integral transmembr ...

s (transporters) that couple the favorable movement of one molecule with its

concentration gradient Fick's laws of diffusion describe diffusion and were first posited by Adolf Fick in 1855 on the basis of largely experimental results. They can be used to solve for the diffusion coefficient, . Fick's first law can be used to derive his second ...

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 an integral membrane protein that uses secondary active transport to move two or more molecules in opposite directions across a phospholipid membrane. It is a type of cotransporter, ...

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 can be classified as IMPs, but not all IMPs are transmembrane proteins. IMPs com ...

known as transporters that move

molecules A molecule is a group of two or more atoms that are held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions that satisfy this criterion. In quantum physics, organic chemistry ...

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 convent ...

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 transmembra ...

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 1,000 to 100,000 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

. Both use

electric potential Electric potential (also called the ''electric field potential'', potential drop, the electrostatic potential) is defined as electric potential energy per unit of electric charge. More precisely, electric potential is the amount of work (physic ...

, chemical gradients, or both to move protons and ions against a concentration gradient. In plants, the

proton A proton is a stable subatomic particle, symbol , Hydron (chemistry), H+, or 1H+ with a positive electric charge of +1 ''e'' (elementary charge). Its mass is slightly less than the mass of a neutron and approximately times the mass of an e ...

is considered a secondary substance, and high proton concentration in the

apoplast The ''apoplast '' is the extracellular space outside of plant cell membranes, especially the fluid-filled cell walls of adjacent cells where water and dissolved material can flow and diffuse freely. Fluid and material flows occurring in any extr ...

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. ...

causes ions to be moved into the

vacuole A vacuole () is a membrane-bound organelle which is present in Plant cell, plant and Fungus, fungal Cell (biology), cells and some protist, animal, and bacterial cells. Vacuoles are essentially enclosed compartments which are filled with water ...

by the proton-sodium antiporter or the proton-calcium antiporter. In plants, sucrose transport is distributed throughout the plant by the proton-pump; the pump 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, a process that uses energy. Since both glucose and sodium are transported in the same direction across the membrane, they are classified as symporters. The glucose transporter system was first hypothesized by Robert K. Crane in 1960.

History

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 irreversibly 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 p ...

and

phosphate Phosphates are the naturally occurring form of the element phosphorus. 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 orthop ...

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 cellular ...

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 othe ...

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 (), Oleh (), or Aleh () is an East Slavic given name. The name is very common in Russia, Ukraine, and Belаrus. Origins ''Oleg'' derives from the Old Norse ''Helgi'' ( Helge), meaning "holy", "sacred", or "blessed". The feminine equival ...

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 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 (electrophysiol ...

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 ...

. 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 cellula ...

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 conven ...

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), referred to as erythrocytes (, with -''cyte'' translated as 'cell' in modern usage) in academia and medical publishing, also known as red cells, erythroid cells, and rarely haematids, are the most common type of blood cel ...

and moves

chloride ion The term chloride refers to a compound or molecule that contains either a chlorine anion (), which is a negatively charged chlorine atom, or a non-charged chlorine atom covalently bonded to the rest of the molecule by a single bond (). The pro ...

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 biochemical ...

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 is a chemical compound with the chemical formula . It is made up of molecules that each have one carbon atom covalent bond, covalently double bonded to two oxygen atoms. It is found in a gas state at room temperature and at norma ...

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 – This specific cotransporter regulates the cell volume by controlling the water and

electrolyte An electrolyte is a substance that conducts electricity through the movement of ions, but not through the movement of electrons. This includes most soluble Salt (chemistry), salts, acids, and Base (chemistry), bases, dissolved in a polar solven ...

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 neuromuscular junction, muscles or glands. Chemical synapses allow neurons to form biological neural ...

. 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 (American English), neurone (British English), or nerve cell, is an excitable cell that fires electric signals called action potentials across a neural network in the nervous system. They are located in the nervous system and help to ...

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 a chemical element; it has Symbol (chemistry), symbol K (from Neo-Latin ) and atomic number19. It is a silvery white metal that is soft enough to easily cut with a knife. Potassium metal reacts rapidly with atmospheric oxygen to ...

and

chloride The term chloride refers to a compound or molecule that contains either a chlorine anion (), which is a negatively charged chlorine atom, or a non-charged chlorine atom covalently bonded to the rest of the molecule by a single bond (). The pr ...

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