Transporter

In medicine, the term "transporter" or transporter proteins refers to cellular functional systems that are capable of actively transporting substances through cell membranes. A distinction must be made between:

• Passive protein-independent transport systems: diffusion, osmosis, filtration or in the form of vesicles which are cut off from the membrane of the endoplasmic reticulum and fuse with the membrane of the target organelles (plasma membrane, canalicular membrane) (happens without consumption of energy, only by a concentration gradient).
• Active transporters: the transport can only take place with energy supply . The substance is transported through the cell membrane by a transporter. A transport even against the concentration gradient is possible with active transporters.

Influx transporters, also known as inward transporters, are transporters that transport substances into the cell. Typical influenza transporters are NAT (norepinephrine transporter), which is responsible for the withdrawal of norepinephrine into the releasing neuron and EMT, the extraneural monoamine transporter, which is responsible for the elimination of about 5% of the released norepinephrine.

Efflux transporters (efflux pumps), also known as outward transporters, are "primary" transporters that carry molecules out of the cell. Efflux transporters are membrane-bound transporters that also have ATPase activity. Membrane ATPases are found in all living organisms. Among other things, they are responsible for the antibiotic resistance of bacteria and for the resistance of fungi to antimycotics.

Furthermore, transporters can also be identified by the direction of substrate transport:

• Uniporter: Uniporters are transporters that transport a substrate in one direction only.
• Co-transporters (Symtransporters; symporters) are transporters that transport both substrates in the same direction
• Antiporters (counter-transporters) are transporters that transport a substrate in one direction and a second in the opposite direction (see figure)

Influx transporter (inward transporter)

• OA-influx transporter (organic anion transporter): With the help of an OA-influx transporter, statins (OATP1B1) are transported from the blood into the liver cell
• OC-influx transporter (organic cation transporter).

Examples for Influx-Transporter:

DMT1 transporter: DMT1 is a divalent influential metal ion transporter, an organic cation transporter that performs the transport of divalent cations through a cell membrane (Johnson DM et al. 2005). Cations such as cadmium ions, magnesium ions and zinc ions are transported. However, the most important function of DMT1 is the transport of divalent iron DMT1 is mainly located in the intestine at the apical membrane of enterocytes. Mutaions in the coding DTM1 gene lead to anaemia (Brissot P et al. 2018)

Efflux transporters (outward transporters): "Efflux transporters" refers to "primary" transporters (primarily active transporters are always also ATPases) that transport molecules out of the cell (efflux). Efflux transporters are membrane-bound transporters that simultaneously exhibit ATPase activity. ATP cleavage provides the energy for the transport. Membrane ATPases are found in all living organisms. Among other things, they are responsible for the antibiotic resistance of bacteria and the resistance of fungi to antimycotics. Since their function was first discovered in the transport of drugs and the resulting drug resistance, some have been termed "multidrug resistance proteins" or MDR-p-glycoproteins (Du D et al. 2018).

• OA efflux transporter refers to an organic anion transporter
• OC- Efflux transporter refers to an organic cation transporter

Examples of Efflux transporters:

An example of OA efflux transporter systems is the large group of ABC transporters (ABC=ATP-binding cassette). The large family of human NBC transporters can be divided into seven subfamilies (NBCA-G) with a total of 49 different genes and 21 different pseudogenes (Kathawala RJ et al. 2015).

ABC transporters are membrane-bound efflux transporters (outward transporters). They always transport endogenous substances such as testosterone, progesterone or pharmaceuticals from the cell into the extracellular space. CFTR is an exception. With the CFTR = Cystic Fibrosis Transmembrane Conductance Regulator, the ABC cassette only controls the opening and closing of a chloride ion channel. Mutations in the CFTR gene lead to the clinical picture of cystic fibrosis. Since the substrates of ABC transporters are transported against a concentration gradient, energy must be expended for the transport process. All ABC transporters (49 are known so far) obtain this energy by binding an ATPase. This means that they themselves hydrolyse ATP. ABC transporters are therefore to be understood as membrane-bound ATPases. ABC transporters play a major role in the development of resistance of bacteria to antibiotics (Theodoulou FL et al. 2015). In plants in the development of resistance to herbicides. Mutations in a coding transporter gene lead to various metabolic diseases. Overexpression of the ABC transporters in tumour tissue can lead to a non-response to chemotherapeutic drugs.

MDR1 transporter (MDR=Multiple Drug Resistance): The MDR1 transporter was the first ABC transportercharacterized in humans. The Multiple Drug Resistance Protein 1 (MDR 1 also called P-glycoprotein or PGp) and the Multidrug Resistance-Related Protein 1 (MRP1) are involved in the transporter. MDR transporters are found, among other things, in the blood-brain barrier, in epithelia of the small intestinal mucosa, but also in tumour cells. In the blood-brain barrier this type of transporter prevents, for example, the central effect of loperamide, an opioid. In tumour cells, high MDR expression leads to an increased tolerance to cytostatic drugs. In intestinal enterocytes, this ABC transporter mediates an active efflux of already resorbed drugs back into intestinal lumen, thus reducing the absorption and bioavailability of these substances (e.g. digoxin, verapamil, cicloporin).

SLC transporter: "SLC" stands for "Solute Carrier". SLC transporters, also belonging to the ABC transporters, mediate "secondary active" or by facilitated diffusion the influx and efflux of drugs and thus the transport through polar cells. For example, a drug is absorbed from the intestinal lumen and then secreted into the blood via SLC transporters. In neurons, they are responsible, among other things, for resuming the transmitter. This function can be inhibited by antidepressants, which thereby inhibit the reabsorption of norepinephrine and serotonin and increase their concentration in the synaptic cleft. SLC transporters are also expressed in liver and kidney parenchyma and CNS.

Transporter systems in the kidney:

• Numerous transporter systems are expressed in the renal tubules. A basolateral Na+/K+-ATPase (under ATP consumption) transports Na+ out of the cell and K+ into the cell. The following transporters are known in the apical parts of the renal tubules:
• SGLT1/SGLT2 transporter (sodium-glucose cotransporter 1/2) an Na+/glucose importer . The Na+ absorption through the apical cell membrane of the main cells of the collection tube (from the lumen of the collection tube into the cell) is mainly via Na+, glucose symporter, Na+, phenylalanine symporter, Na+, phosphate symporter and Na+/K+-ATPase Na+ channels.
• NBC1 transporter: Na+/3HCO3 importer; transports sodium and bicarbonate ions against their chemical gradient from the cell into the renal interstitium.
• NKCC2-Transporter (Na+/K+/2Cl-Cotransporter): There are two subforms, NKCC1 and NKCC2: NKCC1 can be found in all body cells, but mainly in glandular ducts and in the brain (but only during embryogenesis). NKCC1 is located basolateral.
• NKCC2, however, is restricted to the kidney. In the ascending part of the Henle loop it serves to reabsorb sodium and concentrate urine. NKCC2 is apical (towards the lumen). The potassium absorbed in this way can return to the lumen via the ROMK1 channel. This transporter is inhibited by the loop diuretic furosemide. Clinically, furosemide is used, for example, to flush out oedema. However, it should be noted that increased electrolytes such as sodium and potassium are also excreted. In type I Bartter syndrome (very rare hereditary disease with mutations in NKCC2), the function of the furosemid-sensitive Na+/K+/2Cl-cotransporter is disturbed.

SERT (serotonin transporter): SERT, also called 5-hydroxytryptamine transporter 5-HTT, is a protein of the cell membrane that enables the transport of serotonin into the cell. One of the main functions of this transport protein is the removal of released serotonin from the synaptic cleft and thus the termination of serotonin action. The transport of serotonin into the cell (influenza transporter) is driven as a secondary active process by sodium-potassium ATPase (Androutsellis-Theotokis A et al. 2003). Versch. Psychostimulants such as cocaine and MDMA(ecstasy) inhibit its function. Selective inhibitors of the serotonin transporter (selective serotonin reuptake inhibitors, SSRI), are used in the treatment of depression.

Secondary transporters: Secondary transporters or secondary active transporters derive their energy from the electrochemical gradient of ions (mostly Na+), which has been established by primary active transport under ATP hydrolysis. Secondary transporters are not ATPases. The energy transfer is achieved by coupling the downhill transport of Na+ (first substrate) with the uphill transport of e.g. glucose or serotonin (second substrate) (antiporter - see figure).

Interactions with medicinal products:

• Various drugs have the ability to interact with transporter proteins. They are able to induce or inhibit them. This reduces or increases the bioavailability of other drugs transported by the same transporters. Rifampicin and St. John's wort provide examples of such interactions: both induce the expression of the P-glycoprotein (MDR1 transporter), thus reducing the bioavailability of other drugs. Other drugs inhibit "drug transporters" such as Ciclosporin A.
• Cytostatic drug tolerances (cytostatic drug resistances): Cytostatic drug tolerances are usually a multifactorial event. Efflux transporters play a major role in this process by transporting cytostatic drugs out of the tumour cell. Many cytostatic drugs increase the expression of ABC transporters. This leads to a reduced or even complete response of these drugs.

1. Androutsellis-Theotokis A et al (2003) Characterization of a functional bacterial homologue of sodium-dependent neurotransmitter transporters. J Biol Chem 278: 12703-12709.
2. Brissot P et al (2018) Rare anemias due to genetic iron metabolism defects. Mutate Res 777:52-63.
3. Du D et al (2018) Multidrug efflux pumps: structure, function and regulation. Nat Rev microbiol. 16:523-539.
4. Johnson DM et al (2005) Regulation of divalent metal transporter expression in human intestinal epithelial cells following exposure to non-haem iron. FEBS Lett 579:1923-1929.
5. Kathawala RJ et al (2015) The modulation of ABC transporter-mediated multidrug resistance in cancer: a review of the past decade. Drug Resist Update 18:1-17
6. Nine VA et al (2016) MAGE-D2 and the Regulation of Renal Salt Transporters. The New England Journal of Medicine 374: 1888-1890.
7. Theodoulou FL et al. (2015) ABC transporter research: going strong 40 years on. Biochem Soc Trans 43:1033-1040.