The SLC16 gene family—from monocarboxylate transporters (MCTs) to aromatic amino acid transporters and beyond

@article{Halestrap2004TheSG,
  title={The SLC16 gene family—from monocarboxylate transporters (MCTs) to aromatic amino acid transporters and beyond},
  author={Andrew P. Halestrap and David Meredith},
  journal={Pfl{\"u}gers Archiv},
  year={2004},
  volume={447},
  pages={619-628}
}
The monocarboxylate cotransporter (MCT) family now comprises 14 members, of which only the first four (MCT1–MCT4) have been demonstrated experimentally to catalyse the proton-linked transport of metabolically important monocarboxylates such as lactate, pyruvate and ketone bodies. SLC16A10 (T-type amino-acid transporter-1, TAT1) is an aromatic amino acid transporter whilst the other members await characterization. MCTs have 12 transmembrane domains (TMDs) with intracellular N- and C-termini and… 

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References

SHOWING 1-10 OF 81 REFERENCES

The proton-linked monocarboxylate transporter (MCT) family: structure, function and regulation.

There is still much work to be done to characterize the properties of the different MCT isoforms and their regulation, which may have wide-ranging implications for health and disease.

The low-affinity monocarboxylate transporter MCT4 is adapted to the export of lactate in highly glycolytic cells.

Rat MCT4 was identified as the major isoform of white muscle cells, mediating lactate efflux out of glycolytically active myocytes and was sensitive to inhibition by the thiol reagent p-chloromercuribenzoesulphonic acid.

Human Monocarboxylate Transporter 2 (MCT2) Is a High Affinity Pyruvate Transporter*

The finding that co-expression of human MCT1 and MCT2 at the mRNA level in human cancer cell lines, including the hematopoietic lineages HL60, K562, MOLT-4, and Burkitt’s lymphoma Raji, andSolid tumor cells such as SW480, A549, and G361, suggest that the two monocarboxylate transporters have distinct biological roles.

Determination of transport kinetics of chick MCT3 monocarboxylate transporter from retinal pigment epithelium by expression in genetically modified yeast.

MCT3 was highly resistant to a number of "classical" inhibitors of lactate transport, and studies with diethyl pyrocarbonate and p-chloromercuribenzenesulfonate set limitations on the locus of potential residues involved in the critical site of lactates translocation.

Characterisation of human monocarboxylate transporter 4 substantiates its role in lactic acid efflux from skeletal muscle

The characterisation of MCT4 expressed in Xenopus oocytes shows that the protein was correctly targeted to the plasma membrane and rates of substrate transport were determined from the rate of intracellular acidification monitored with the pH‐sensitive dye 2′,7′‐bis‐( carboxyethyl)‐5(6)‐carboxyfluorescein (BCECF).

Transport of lactate and other monocarboxylates across mammalian plasma membranes.

There are distinct Na(+)-monocarboxylate cotransporters on the luminal surface of intestinal and kidney epithelia, which enable active uptake of lactate, pyruvate, and ketone bodies in these tissues.

Characterization of the high-affinity monocarboxylate transporter MCT2 in Xenopus laevis oocytes.

It is suggested that cells which express MCT2 preferentially use lactate and ketone bodies as energy sources, and could be inhibited by alpha-cyano-4-hydroxycinnamate, anion-channel inhibitors and flavonoids.

Cloning and sequencing of four new mammalian monocarboxylate transporter (MCT) homologues confirms the existence of a transporter family with an ancient past.

The identification of new human MCT homologues in the database of expression sequence tags and the cloning and sequencing of four new full-length MCT-like sequences from human cDNA libraries are reported, which are denoted MCT3, MCT4, M CT5 and MCT6.
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