Cotransporter

Source: Wikipedia, the free encyclopedia.

Cotransporters are a subcategory of

Uniporters are also transporters but move only one type of molecule down its concentration gradient and are not classified as cotransporters.[1]

Basic difference between the cotransporters known as antiporters and symporters, and the uniporter transporter.

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.[2]

Cotransporters can be classified as

Proton gradient moves the ions into the vacuole 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 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.[2][3]

History

Dr Robert K. Crane and his sketch for coupled cotransport

Dr.

glucose-6-phosphate biochemistry, carbon dioxide fixation, hexokinase and phosphate 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.[4]

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 and is powered by the energy derived from the concentration gradient of the ions/molecules across the membrane the cotransporter protein is integrated within.[1]

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).[5] 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 in 1966.[6] 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.[1] 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.[5]

Types

antiporter
symporter

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.

cation antiporter.[7]

Cells also contain

concentration gradient of the two ions. The AE1 antiporter is essential in the removal of carbon dioxide waste that is converted to bicarbonate inside the erythrocyte.[8]

Symporters

In contrast to antiporters, symporters move ions or molecules in the same direction.

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.[9][10]

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.[11][12]

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.[11][13]

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.[11][14]

Na-K-2Cl symporter – This specific cotransporter regulates the cell volume by controlling the water and electrolyte content within the cell.[15] The Na-K-2Cl Cotransporter is vital in salt secretion in secretory epithelia cells along with renal salt reabsorption.[16] 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.[17]

synaptic cleft. The SLC6A1 gene encodes GABA transporters.[18] The transporters are electrogenic and couples 2 Na+, 1 Cl− and 1 GABA for inward translocation.[11][19]

neuronal tissue and the other three can be found in various tissues throughout the body. This cotransporter family controls the concentration levels of potassium and chloride 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.[20]

Associated diseases

Table 1: List of diseases related to transporters.[21]

Transporter Symbols/Names Relevant Diseases
4F2HC, SLC3A2 Lysinuric
ABC-1, ABC1 Tangier disease
ABC7, hABC7 X-linked sideroblastic anemia
ABCR
Fundus flavimaculatus
AE1, SLC4A1
ovalocytosis, hemolytic anemia, spherocytosis, renal tubular acidosis
AE2, SLC4A2 congenital chloroidorrhea
AE3, SLC4A3 congenital chloroidorrhea
ALDR Adrenoleukodystrophy
ANK ankylosis (calcification); arthritis accompanied by mineral deposition, formation of bony outgrowths, and joint destruction
Aralar-like, SLC25A13 adult-onset type II citrullinemia
ATBo, SLC1A5, hATBo, ASCT2, AAAT
Neurodegeneration
BCMP1, UCP4, SLC25A14 HHH
CFTR Cystic fibrosis
CTR-1, SLC31A1 Menkes/
Wilsons disease
CTR-2, SLC31A2 Menkes/Wilsons disease, X-linked hypophosphatemia
DTD, SLC26A2 chondrodysplasias/ Diastrophic dysplasia
EAAT1, SLC1A3, GLAST1
Amyotrophic lateral sclerosis
EAAT2, SLC1A2, GLT-1 Neurodegeneration, Dicarboxylic aminoaciduria
EAAT3, SLC1A1, EAAC1 Neurodegeneration
EAAT4, SLC1A6 Neurodegeneration
EAAT5, SLC1A7 Neurodegeneration
FIC1 Progressive familial intrahepatic cholestasis
FOLT, SLC19A1, RFC1 Folate malabsorption/megaloblastic anemia
GLUT1, SLC2A1 low CNS glucose causing
diabetes mellitus
, defect in glucose transport across the blood-brain barrier
GLUT2, SLC2A2 low CNS glucose causing seizures, Fanconi-Bickel syndrome, Glycogen storage disease type Id, Non-insulin-dependent diabetes mellitus (NIDDM)
GLUT3, SLC2A3 low CNS glucose causing seizures, Fanconi-Bickel syndrome, Glycogen storage disease type Id, Non-insulin-dependent diabetes mellitus (NIDDM)
GLUT4, SLC2A4 low CNS glucose causing seizures, Fanconi-Bickel syndrome, Glycogen storage disease type Id, Non-insulin-dependent diabetes mellitus (NIDDM)
GLUT5, SLC2A5 Isolated fructose malabsorption
HET
hemochromatosis
HTT, SLC6A4 anxiety-related traits
LAT-2, SLC7A6 Lysinuric protein intolerance
LAT-3, SLC7A7 lysinuric protein intolerance
MDR1 human cancers
MDR2, MDR3 Familia intrahepatic cholestasis
MRP1 human cancers
NBC Down syndrome
NBC1, SLC4A4 renal tubular acidosis
NBC3, SLC4A7 congenital hypothyroidism
NCCT, SLC12A3, TSC Gitelman syndrome
NHE2, SLC9A2
Microvillus inclusion disease
NHE3, SLC9A3/3P Microvillus inclusion disease
NIS, SLC5A5 congenital hypothyroidism
NKCC1, SLC12A2 gitelman syndrome
NKCC2, SLC12A1 Bartter syndrome
NORTR
velocardiofacial syndrome
NRAMP2, DCT1, SLC11A2, Attention deficit hyperactivity disorder
NTCP2, ISBT, SLC10A2 primary bile acid malabsorption (PBAM)
OCTN2, SLC22A5 systemic carnitine deficiency (progressive
sudden infant death syndrome
)
ORNT1, SLC25A15 HHH
PMP34, SLC25A17
Graves disease
rBAT, SLC3A1, D2 cystinuria
SATT, SLC1A4, ASCT1 Neurodegeneration
SBC2 hypocitraturia
SERT various mental disorders
SGLT1, SLC5A1 renal
glucosuria
/ glucose-galactose malabsorption
SGLT2, SLC5A2 renal glucosuria
SMVT, SLC5A6 anxiety-related traits, depression
TAP1 juvenile onset psoriasis
y+L Type I cystinuria

See also

References

  1. ^
    ISBN 978-1-4292-3413-9
    .
  2. ^
    PMID 10213785
    .
  3. PMID 18660845
    .
  4. PMID 23525627
    .
  5. ^
    PMID 21190656
    .
  6. S2CID 4178898
    .
  7. S2CID 6963309
    .
  8. ISBN 978-0716737063
    .
  9. S2CID 41985805
    .
  10. PMID 8599647
    .
  11. ^ a b c d Physiologyweb. "Secondary Active Transport". Physiologyweb. Retrieved 4 December 2013.
  12. PMID 15546855
    .
  13. PMID 23398154
    .
  14. PMID 22011571
    .
  15. S2CID 42069918
    .
  16. PMID 7943281
    .
  17. S2CID 21998913
    .
  18. ^ OMIM Entry. "137165 - SOLUTE CARRIER FAMILY 6 (NEUROTRANSMITTER TRANSPORTER, GABA), MEMBER 1; SLC6A1". Johns Hopkins University. Retrieved 8 December 2013.
  19. ^ GeneCads. "SLC6A11 Gene". Weizmann Institute of Science. Retrieved 8 December 2013.
  20. PMID 10913127
    .
  21. ^ "Membrane Transporter-Related Diseases « Membrane Transporter Database for Personalized Medicine". pharmtao.com.
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