scholarly journals Clinical and Functional Relevance of the Monocarboxylate Transporter Family in Disease Pathophysiology and Drug Therapy

2018 ◽  
Vol 11 (4) ◽  
pp. 352-364 ◽  
Author(s):  
Pascale Fisel ◽  
Elke Schaeffeler ◽  
Matthias Schwab
Keyword(s):  
Drug Therapy ◽  
Monocarboxylate Transporter ◽  
Transporter Family ◽  
Functional Relevance

scholarly journals Mechanism(s) of butyrate transport in Caco-2 cells: role of monocarboxylate transporter 1

2000 ◽  
Vol 279 (4) ◽  
pp. G775-G780 ◽  
Author(s):  
Christos Hadjiagapiou ◽  
Larry Schmidt ◽  
Pradeep K. Dudeja ◽  
Thomas J. Layden ◽  
Krishnamurthy Ramaswamy
Keyword(s):  
Short Chain Fatty Acid ◽  
Rnase Protection Assay ◽  
Significant Inhibition ◽  
Monocarboxylate Transporter ◽  
Rnase Protection ◽  
Monocarboxylate Transporter 1 ◽  
Antisense Orientation ◽  
Transporter Family ◽  
Saturation Kinetics

The short-chain fatty acid butyrate was readily taken up by Caco-2 cells. Transport exhibited saturation kinetics, was enhanced by low extracellular pH, and was Na+independent. Butyrate uptake was unaffected by DIDS; however, α-cyano-4-hydroxycinnamate and the butyrate analogs propionate and l-lactate significantly inhibited uptake. These results suggest that butyrate transport by Caco-2 cells is mediated by a transporter belonging to the monocarboxylate transporter family. We identified five isoforms of this transporter, MCT1, MCT3, MCT4, MCT5, and MCT6, in Caco-2 cells by PCR, and MCT1 was found to be the most abundant isoform by RNase protection assay. Transient transfection of MCT1, in the antisense orientation, resulted in significant inhibition of butyrate uptake. The cells fully recovered from this inhibition by 5 days after transfection. In conclusion, our data showed that the MCT1 transporter may play a major role in the transport of butyrate into Caco-2 cells.

Significance of Short Chain Fatty Acid Transport by Members of the Monocarboxylate Transporter Family (MCT)

2012 ◽  
Vol 37 (11) ◽  
pp. 2562-2568 ◽  
Author(s):  
Ivano Moschen ◽  
Angelika Bröer ◽  
Sandra Galić ◽  
Florian Lang ◽  
Stefan Bröer
Keyword(s):  
Fatty Acid ◽  
Short Chain Fatty Acid ◽  
Chain Fatty Acid ◽  
Short Chain ◽  
Monocarboxylate Transporter ◽  
Fatty Acid Transport ◽  
Acid Transport ◽  
Transporter Family

scholarly journals Transport of lactate and pyruvate in the intraerythrocytic malaria parasite, Plasmodium falciparum

2001 ◽  
Vol 355 (3) ◽  
pp. 733-739 ◽  
Author(s):  
Jemma L. ELLIOTT ◽  
Kevin J. SALIBA ◽  
Kiaran KIRK
Keyword(s):  
Plasmodium Falciparum ◽  
Malaria Parasite ◽  
Direct Evidence ◽  
Monocarboxylate Transporter ◽  
Human Malaria Parasite ◽  
Transporter Family ◽  
Parasite Plasmodium ◽  
Parasite Plasmodium Falciparum ◽  
Lactate And Pyruvate ◽  
Higher Eukaryotes

The mature, intraerythrocytic form of the human malaria parasite, Plasmodium falciparum, is reliant on glycolysis for its energetic requirements. It produces large quantities of lactic acid, which have to be removed from the parasite's cytosol to maintain the cell's integrity and metabolic viability. Here we show that the monocarboxylates lactate and pyruvate are both transported across the parasite's plasma membrane via a H+/monocarboxylate symport process that is saturable and inhibited by the bioflavonoid phloretin. The results provide direct evidence for the presence at the parasite surface of a H+-coupled monocarboxylate transporter with features in common with members of the MCT (monocarboxylate transporter) family of higher eukaryotes.

scholarly journals Localization of members of MCT monocarboxylate transporter family Slc16 in the kidney and regulation during metabolic acidosis

2010 ◽  
Vol 299 (1) ◽  
pp. F141-F154 ◽  
Author(s):  
Helen M. Becker ◽  
Nilufar Mohebbi ◽  
Angelica Perna ◽  
Vadivel Ganapathy ◽  
Giovambattista Capasso ◽  
...  
Keyword(s):  
Metabolic Acidosis ◽  
Mrna Level ◽  
Distal Tubule ◽  
Transient Increase ◽  
Monocarboxylate Transporter ◽  
Thick Ascending Limb ◽  
Intercalated Cells ◽  
Transporter Family ◽  
And Function ◽  
Lactate Excretion

The monocarboxylate transporter family (MCT) comprises 14 members with distinct transport properties and tissue distribution. The kidney expresses several members of the MCT family, but only little is known about their exact distribution and function. Here, we investigated selected members of the MCT family in the mouse kidney. MCT1, MCT2, MCT7, and MCT8 localized to basolateral membranes of the epithelial cells lining the nephron. MCT1 and MCT8 were detected in proximal tubule cells whereas MCT7 and MCT2 were located in the thick ascending limb and the distal tubule. CD147, a β-subunit of MCT1 and MCT4, showed partially overlapping expression with MCT1 and MCT2. However, CD147 was also found in intercalated cells. We also detected SMCT1 and SMCT2, two Na+-dependent monocarboxylate cotransporters, on the luminal membrane of type A intercalated cells. Moreover, mice were given an acid load for 2 and 7 days. Acidotic animals showed a marked but transient increase in urinary lactate excretion. During acidosis, a downregulation of MCT1, MCT8, and SMCT2 was observed at the mRNA level, whereas MCT7 and SMCT1 showed increased mRNA abundance. Only MCT7 showed lower protein abundance whereas all other transporters remained unchanged. In summary, we describe for the first time the localization of various MCT transporters in mammalian kidney and demonstrate that metabolic acidosis induces a transient increase in urinary lactate excretion paralleled by lower MCT7 protein expression.

scholarly journals Renal Localization and Characterization of Monocarboxylate Transporter Family Member Slc16a14

2015 ◽  
Vol 29 (S1) ◽  
Author(s):  
Thomas Knöpfel ◽  
Alexander Atanassoff ◽  
Nicole Kampik ◽  
Nati Hernando ◽  
Carsten Wagner ◽  
...  
Keyword(s):  
Family Member ◽  
Monocarboxylate Transporter ◽  
Transporter Family

scholarly journals Basigin drives intracellular accumulation of l-lactate by harvesting protons and substrate anions

PLoS ONE ◽  
2021 ◽  
Vol 16 (3) ◽  
pp. e0249110
Author(s):  
Anna-Lena Köpnick ◽  
Annika Jansen ◽  
Katharina Geistlinger ◽  
Nathan Hugo Epalle ◽  
Eric Beitz
Keyword(s):  
Disulfide Bridge ◽  
Monocarboxylate Transporter ◽  
Intracellular Accumulation ◽  
Biophysical Properties ◽  
Entry Site ◽  
Cytosolic Ph ◽  
Domain Identification ◽  
Surface Patches ◽  
Transporter Family ◽  
Lactate Uptake

Transmembrane transport of l-lactate by members of the monocarboxylate transporter family, MCT, is vital in human physiology and a malignancy factor in cancer. Interaction with an accessory protein, typically basigin, is required to deliver the MCT to the plasma membrane. It is unknown whether basigin additionally exerts direct effects on the transmembrane l-lactate transport of MCT1. Here, we show that the presence of basigin leads to an intracellular accumulation of l-lactate 4.5-fold above the substrate/proton concentrations provided by the external buffer. Using basigin truncations we localized the effect to arise from the extracellular Ig-I domain. Identification of surface patches of condensed opposite electrostatic potential, and experimental analysis of charge-affecting Ig-I mutants indicated a bivalent harvesting antenna functionality for both, protons and substrate anions. From these data, and determinations of the cytosolic pH with a fluorescent probe, we conclude that the basigin Ig-I domain drives lactate uptake by locally increasing the proton and substrate concentration at the extracellular MCT entry site. The biophysical properties are physiologically relevant as cell growth on lactate media was strongly promoted in the presence of the Ig-I domain. Lack of the domain due to shedding, or misfolding due to breakage of a stabilizing disulfide bridge reversed the effect. Tumor progression according to classical or reverse Warburg effects depends on the transmembrane l-lactate distribution, and this study shows that the basigin Ig-I domain is a pivotal determinant.

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

1998 ◽  
Vol 329 (2) ◽  
pp. 321-328 ◽  
Author(s):  
T. Nigel PRICE ◽  
N. Vicky JACKSON ◽  
P. Andrew HALESTRAP
Keyword(s):  
Monocarboxylate Transporter ◽  
Cdna Libraries ◽  
Sequence Motifs ◽  
Intracellular Loop ◽  
Cloning And Sequencing ◽  
Sequence Alignments ◽  
Yeast Saccharomyces Cerevisiae ◽  
Multiple Sequence ◽  
Conserved Sequence ◽  
Transporter Family

Measurement of monocarboxylate transport kinetics in a range of cell types has provided strong circumstantial evidence for a family of monocarboxylate transporters (MCTs). Two mammalian MCT isoforms (MCT1 and MCT2) and a chicken isoform (REMP or MCT3) have already been cloned, sequenced and expressed, and another MCT-like sequence (XPCT) has been identified. Here we report 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, which we have denoted MCT3, MCT4, MCT5 and MCT6. Northern blotting revealed a unique tissue distribution for the expression of mRNA for each of the seven putative MCT isoforms (MCT1-MCT6 and XPCT). All sequences were predicted to have 12 transmembrane (TM) helical domains with a large intracellular loop between TM6 and TM7. Multiple sequence alignments showed identities ranging from 20% to 55%, with the greatest conservation in the predicted TM regions and more variation in the C-terminal than the N-terminal region. Searching of additional sequence databases identified candidate MCT homologues from the yeast Saccharomyces cerevisiae, the nematode worm Caenorhabditis elegans and the archaebacterium Sulfolobus solfataricus. Together these sequences constitute a new family of transporters with some strongly conserved sequence motifs, the possible functions of which are discussed.

scholarly journals The loop between helix 4 and helix 5 in the monocarboxylate transporter MCT1 is important for substrate selection and protein stability

2003 ◽  
Vol 376 (2) ◽  
pp. 413-422 ◽  
Author(s):  
Sandra GALIĆ ◽  
Hans-Peter SCHNEIDER ◽  
Angelika BRÖER ◽  
Joachim W. DEITMER ◽  
Stefan BRÖER
Keyword(s):  
Mammalian Cells ◽  
Ketone Bodies ◽  
Monocarboxylate Transporter ◽  
Substrate Selection ◽  
Transport Activity ◽  
Complete Inactivation ◽  
Transporter Family ◽  
Monocarboxylate Transport ◽  
Critical Residues ◽  
Signature Sequence

Transport of lactate, pyruvate and the ketone bodies acetoacetate and β-hydroxybutyrate, is mediated in most mammalian cells by members of the monocarboxylate transporter family (SLC16). A conserved signature sequence has been identified in this family, which is located in the loop between helix 4 and helix 5 and extends into helix 5. We have mutated residues in this signature sequence in the rat monocarboxylate transporter (MCT1) to elucidate the significance of this region for monocarboxylate transport. Mutation of R143 and G153 resulted in complete inactivation of the transporter. For the MCT1(G153V) mutant this was explained by a failure to reach the plasma membrane. The lack of transport activity of MCT1(R143Q) could be partially rescued by the conservative exchange R143H. The resulting mutant transporter displayed reduced stability, a decreased Vmax of lactate transport but not of acetate transport, and an increased stereoselectivity. Mutation of K137, K141 and K142 indicated that only K142 played a significant role in the transport mechanism. Mutation of K142 to glutamine resulted in an increase of the Km for lactate from 5 mM to 12 mM. In contrast with MCT1(R143H), MCT1(K142Q) was less stereoselective than the wild-type. A mechanism is proposed that includes all critical residues.

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