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Pflügers Archiv

, Volume 447, Issue 5, pp 619–628 | Cite as

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

  • Andrew P. Halestrap
  • David Meredith
The ABC of Solute Carriers Guest Editor: Matthias A. Hediger

Abstract

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 a large intracellular loop between TMDs 6 and 7. MCT1 and MCT4 require a monotopic ancillary protein, CD147, for expression of functional protein at the plasma membrane. Lactic acid transport across the plasma membrane is fundamental for the metabolism of and pH regulation of all cells, removing lactic acid produced by glycolysis and allowing uptake by those cells utilizing it for gluconeogenesis (liver and kidney) or as a respiratory fuel (heart and red muscle). The properties of the different MCT isoforms and their tissue distribution and regulation reflect these roles.

Keywords

Lactate Intracellular pH Glycolysis monocarboxylate transporter (MCT) 

Notes

Acknowledgements

Work performed in the authors' laboratories was supported by grants from the Medical Research Council, The Wellcome Trust and The British Heart Foundation.

References

  1. 1.
    Baker SK, Tarnopolsky MA, Bonen A (2001) Expression of MCT1 and MCT4 in a patient with mitochondrial myopathy. Muscle Nerve 24:394–398CrossRefPubMedGoogle Scholar
  2. 2.
    Bergersen L, Johannsson E, Veruki ML, Nagelhus EA, Halestrap AP, Sejersted OM, Ottersen OP (1999) Cellular and subcellular expression of monocarboxylate transporters in the pigment epithelium and retina of the rat. Neuroscience 90:319–331CrossRefPubMedGoogle Scholar
  3. 3.
    Bergersen L, Waerhaug O, Helm J, Thomas M, Laake P, Davies AJ, Wilson MC, Halestrap AP, Ottersen OP (2001) A novel postsynaptic density protein: the monocarboxylate transporter MCT2 is co-localized with delta-glutamate receptors in postsynaptic densities of parallel fiber-Purkinje cell synapses. Exp Brain Res 136:523–534CrossRefPubMedGoogle Scholar
  4. 4.
    Bergersen L, Rafiki A, Ottersen OP (2002) Immunogold cytochemistry identifies specialized membrane domains for monocarboxylate transport in the central nervous system. Neurochem Res 27:89–96CrossRefPubMedGoogle Scholar
  5. 5.
    Biswas C, Zhang Y, DeCastro R, Guo H, Nakamura T, Kataoka H, Nabeshima K (1995) The human tumor cell-derived collagenase stimulatory factor (renamed EMMPRIN) is a member of the immunoglobulin superfamily. Cancer Res 55:434–439PubMedGoogle Scholar
  6. 6.
    Bonen A, Miskovic D, Tonouchi M, Lemieux K, Wilson MC, Marette A, Halestrap AP (2000) Abundance and subcellular distribution of MCT1 and MCT4 in heart and fast-twitch skeletal muscles. Am J Physiol 278:E1067–E1077Google Scholar
  7. 7.
    Bonen A, Tonouchi M, Miskovic D, Heddle C, Heikkila JJ, Halestrap AP (2000) Isoform-specific regulation of the lactate transporters MCT1 and MCT4 by contractile activity. Am J Physiol 279:E1131–E1138Google Scholar
  8. 8.
    Bröer S, Schneider HP, Bröer A, Rahman B, Hamprecht B, Deitmer JW (1998) Characterization of the monocarboxylate transporter 1 expressed in Xenopus laevis oocytes by changes in cytosolic pH. Biochem J 333:167–174PubMedGoogle Scholar
  9. 9.
    Bröer S, Bröer A, Schneider H-P, Stegen C, Halestrap AP, Deitmer JW (1999) Characterisation of the high-affinity monocarboxylate transporter MCT2 in Xenopus laevis oocytes. Biochem J 341:529–535PubMedGoogle Scholar
  10. 10.
    Carpenter L, Halestrap AP (1994) The kinetics, substrate and inhibitor specificity of the lactate transporter of Ehrlich-Lettre tumour cells studied with the intracellular pH indicator BCECF. Biochem J 304:751–760PubMedGoogle Scholar
  11. 11.
    Carpenter L, Poole RC, Halestrap AP (1996) Cloning and sequencing of the monocarboxylate transporter from mouse Ehrlich Lettre tumour cell confirms its identity as MCT1 and demonstrates that glycosylation is not required for MCT1 function. Biochim Biophys Acta 1279:157–163CrossRefPubMedGoogle Scholar
  12. 12.
    Cuff MA, Lambert DW, Shirazi-Beechey SP (2002) Substrate-induced regulation of the human colonic monocarboxylate transporter, MCT1. J Physiol (Lond) 539:361–371Google Scholar
  13. 13.
    Deuticke B (1982) Monocarboxylate transport in erythrocytes. J Membr Biol 70:89–103PubMedGoogle Scholar
  14. 14.
    Dimmer KS, Friedrich B, Lang F, Deitmer JW, Bröer S (2000) The low-affinity monocarboxylate transporter MCT4 is adapted to the export of lactate in highly glycolytic cells. Biochem J 350:219–227CrossRefPubMedGoogle Scholar
  15. 15.
    Enoki T, Yoshida Y, Hatta H, Bonen A (2003) Exercise training alleviates MCT1 and 4 reductions in heart and skeletal muscles of STZ-induced diabetic rats. J Appl Physiol DOI: 10.1152/japplphysiol.01155.2002Google Scholar
  16. 16.
    Fishbein WN (1986) Lactate transporter defect: a new disease of muscle. Science 234:1254–1256PubMedGoogle Scholar
  17. 17.
    Froberg MK, Gerhart DZ, Enerson BE, Manivel C, Guzman-Paz M, Seacotte N, Drewes LR (2001) Expression of monocarboxylate transporter MCTI in normal and neoplastic human CNS tissues. Neuroreport 12:761–765PubMedGoogle Scholar
  18. 18.
    Garcia CK, Li X, Luna J, Francke U (1994) cDNA cloning of the human monocarboxylate transporter 1 and chromosomal localization of the SLC16A1 locus to 1p13.2-p12. Genomics 23:500–503PubMedGoogle Scholar
  19. 19.
    Garcia CK, Brown MS, Pathak RK, Goldstein JL (1995) cDNA cloning of MCT2, a second monocarboxylate transporter expressed in different cells than MCT1. J Biol Chem 270:1843–1849PubMedGoogle Scholar
  20. 20.
    Gerhart DZ, Leino RL, Drewes LR (1999) Distribution of monocarboxylate transporters MCT1 and MCT2 in rat retina. Neuroscience 92:367–375CrossRefPubMedGoogle Scholar
  21. 21.
    Green H, Halestrap A, Mockett C, O'Toole D, Grant S, Ouyang J (2002) Increases in muscle MCT are associated with reductions in muscle lactate after a single exercise session in humans. Am J Physiol 282:E154–E160Google Scholar
  22. 22.
    Grollman EF, Philp NJ, McPhie P, Ward RD, Sauer B (2000) Determination of transport kinetics of chick MCT3 monocarboxylate transporter from retinal pigment epithelium by expression in genetically modified yeast. Biochemistry 39:9351–9357CrossRefPubMedGoogle Scholar
  23. 23.
    Hajduch E, Heyes RR, Watt PW, Hundal HS (2000) Lactate transport in rat adipocytes: identification of monocarboxylate transporter 1 (MCT1) and its modulation during streptozotocin-induced diabetes. FEBS Lett 479:89–92CrossRefPubMedGoogle Scholar
  24. 24.
    Halestrap AP, Price NT (1999) The proton-linked monocarboxylate transporter (MCT) family: structure, function and regulation. Biochem J 343:281–299PubMedGoogle Scholar
  25. 25.
    Hatta H, Tonouchi M, Miskovic D, Wang YX, Heikkila JJ, Bonen A (2001) Tissue-specific and isoform-specific changes in MCT1 and MCT4 in heart and soleus muscle during a 1-yr period. Am J Physiology 281:E749–E756Google Scholar
  26. 26.
    Hosoya K, Kondo T, Tomi M, Takanaga H, Ohtsuki S, Terasaki T (2001) MCT1-mediated transport of L-lactic acid at the inner blood-retinal barrier: a possible route for delivery of monocarboxylic acid drugs to the retina. Pharm Res 18:1669–1676CrossRefPubMedGoogle Scholar
  27. 27.
    Jackson VN, Price NT, Carpenter L, Halestrap AP (1997) Cloning of the monocarboxylate transporter isoform MCT2 from rat testis provides evidence that expression in tissues is species-specific and may involve post-transcriptional regulation. Biochem J 324:447–453PubMedGoogle Scholar
  28. 28.
    Johannsson E, Lunde PK, Heddle C, Sjaastad I, Thomas MJ, Bergersen L, Halestrap AP, Blackstad TW, Ottersen OP, Sejersted OM (2001) Upregulation of the cardiac monocarboxylate transporter MCT1 in a rat model of congestive heart failure. Circulation 104:729–734PubMedGoogle Scholar
  29. 29.
    Juel C, Halestrap AP (1999) Lactate transport in skeletal muscle—role and regulation of the monocarboxylate transporter. J Physiol (Lond) 517:633–642Google Scholar
  30. 30.
    Kim CM, Goldstein JL, Brown MS (1992) cDNA cloning of MEV, a mutant protein that facilitates cellular uptake of mevalonate, and identification of a point mutation responsible for its gain in function. J Biol Chem 267:23113–23121PubMedGoogle Scholar
  31. 31.
    Kim DK, Kanai Y, Chairoungdua A, Matsuo H, Cha SH, Endou H (2001) Expression cloning of a Na+-independent aromatic amino acid transporter with structural similarity to H+/monocarboxylate transporters. J Biol Chem 276:17221–17228PubMedGoogle Scholar
  32. 32.
    Kim DK, Kanai Y, Matsuo H, Kim JY, Chairoungdua A, Kobayashi Y, Enomoto A, Cha SH, Goya T, Endou H (2001) The human T-type amino acid transporter-1: characterization, gene organization, and chromosomal location. Genomics 79:95–103CrossRefGoogle Scholar
  33. 33.
    Kim-Garcia C, Goldstein JL, Pathak RK, Anderson RGW, Brown MS (1994) Molecular characterization of a membrane transporter for lactate, pyruvate, and other monocarboxylates—implications for the Cori cycle. Cell 76:865–873PubMedGoogle Scholar
  34. 34.
    Kirk P, Wilson MC, Heddle C, Brown MH, Barclay AN, Halestrap AP (2000) CD147 is tightly associated with lactate transporters MCT1 and MCT4 and facilitates their cell surface expression. EMBO J 19:3896–3904Google Scholar
  35. 35.
    Lafreniere RG, Carrel L, Willard HF (1994) A novel transmembrane transporter encoded by the XPCT gene in Xq13.2. Hum Mol Gen 3:1133–1139PubMedGoogle Scholar
  36. 36.
    Lambert DW, Wood IS, Ellis A, Shirazi-Beechey SP (2002) Molecular changes in the expression of human colonic nutrient transporters during the transition from normality to malignancy. Br J Cancer 86:1262–1269CrossRefPubMedGoogle Scholar
  37. 37.
    Leino RL, Gerhart DZ, Drewes LR (1999) Monocarboxylate transporter (MCT1) abundance in brains of suckling and adult rats: a quantitative electron microscopic immunogold study. Dev Brain Res 113:47–54CrossRefGoogle Scholar
  38. 38.
    Leino RL, Gerhart DZ, Duelli R, Enerson BE, Drewes LR (2001) Diet-induced ketosis increases monocarboxylate transporter (MCT1) levels in rat brain. Neurochem Int 38:519–527CrossRefPubMedGoogle Scholar
  39. 39.
    Lin RY, Vera JC, Chaganti RSK, Golde DW (1998) Human monocarboxylate transporter 2 (MCT2) is a high affinity pyruvate transporter. J Biol Chem 273:28959–28965CrossRefPubMedGoogle Scholar
  40. 40.
    Manning Fox JE, Meredith D, Halestrap AP (2000) Characterisation of human monocarboxylate transporter 4 substantiates its role in lactic acid efflux from skeletal muscle. J Physiol (Lond) 529:285–293Google Scholar
  41. 41.
    Meredith D, Halestrap AP (2000) OX47 (basigin) may act as a chaperone for expression of the monocarboxylate transporter MCT1 at the plasma membrane of Xenopus laevis oocytes (abstract). J Physiol (Lond) 526P:23PGoogle Scholar
  42. 42.
    Meredith D, Roberts M, Halestrap AP (1999) Both K290 and K413 are essential for DIDS covalent modification of the rat proton-linked monocarboxylate (lactate) transporter MCT1 expressed in Xenopus laevis oocytes (abstract). J Physiol (Lond) 517P:25PGoogle Scholar
  43. 43.
    Meredith D, Bell P, McClure B, Wilkins R (2002) Functional and molecular characterisation of lactic acid transport in bovine articular chondrocytes. Cell Physiol Biochem 12:227–234CrossRefPubMedGoogle Scholar
  44. 44.
    Merezhinskaya N, Fishbein WN (1997) Muscle monocarboxylate transporter (MCT1) mutations in 5 patients with red cell (RBC) lactate transport deficiency (LTD). FASEB J 11:656Google Scholar
  45. 45.
    Merezhinskaya N, Fishbein WN, Davis JI, Foellmer JW (2000) Mutations in MCT1 cDNA in patients with symptomatic deficiency in lactate transport. Muscle Nerve 23:90–97CrossRefPubMedGoogle Scholar
  46. 46.
    Nehme CL, Fayos BE, Bartles JR (1995) Distribution of the integral plasma membrane glycoprotein CE9 (MRC OX-47) among rat tissues and its induction by diverse stimuli of metabolic activation. Biochem J 310:693–698PubMedGoogle Scholar
  47. 47.
    Okamura A, Emoto A, Koyabu N, Ohtani H, Sawada Y (2002) Transport and uptake of nateglinide in Caco-2 cells and its inhibitory effect on human monocarboxylate transporter MCT1. Br J Pharmacol 137:391–399CrossRefPubMedGoogle Scholar
  48. 48.
    Okamura H, Spicer SS, Schulte BA (2001) Developmental expression of monocarboxylate transporter in the gerbil inner ear. Neuroscience 107:499–505CrossRefPubMedGoogle Scholar
  49. 49.
    Philp NJ, Yoon H, Grollman EF (1998) Monocarboxylate transporter MCT1 is located in the apical membrane and MCT3 in the basal membrane of rat RPE Am J Physiol 274:R1824–R1828Google Scholar
  50. 50.
    Philp NJ, Yoon HY, Lombardi L (2001) Mouse MCT3 gene is expressed preferentially in retinal pigment and choroid plexus epithelia. Am J Physiol 280:C1319–C1326Google Scholar
  51. 51.
    Pierre K, Pellerin L, Debernardi R, Riederer BM, Magistretti PJ (2000) Cell-specific localization of monocarboxylate transporters, MCT1 and MCT2, in the adult mouse brain revealed by double immunohistochemical labeling and confocal microscopy. Neuroscience 100:617–627CrossRefPubMedGoogle Scholar
  52. 52.
    Pierre K, Magistretti PJ, Pellerin L (2002) MCT2 is a major neuronal monocarboxylate transporter in the adult mouse brain. J Cereb Blood Flow Metab 22:586–595PubMedGoogle Scholar
  53. 53.
    Poole RC, Halestrap AP (1991) Reversible and irreversible inhibition, by stilbenedisulphonates, of lactate transport into rat erythrocytes—identification of some new high-affinity inhibitors. Biochem J 275:307–312PubMedGoogle Scholar
  54. 54.
    Poole RC, Halestrap AP (1992) Identification and partial purification of the erythrocyte lactate transporter. Biochem J 283:855–862PubMedGoogle Scholar
  55. 55.
    Poole RC, Halestrap AP (1993) Transport of lactate and other monocarboxylates across mammalian plasma membranes. Am J Physiol 264:C761–C782PubMedGoogle Scholar
  56. 56.
    Poole RC, Halestrap AP (1994) N-Terminal protein sequence analysis of the rabbit erythrocyte lactate transporter suggests identity with the cloned monocarboxylate transport protein MCT1. Biochem J 303:755–759PubMedGoogle Scholar
  57. 57.
    Poole RC, Sansom CE, Halestrap AP (1996) Studies of the membrane topology of the rat erythrocyte H+/lactate cotransporter (MCT1). Biochem J 320:817–824PubMedGoogle Scholar
  58. 58.
    Price NT, Jackson VN, Halestrap AP (1998) Cloning and sequencing of four new mammalian monocarboxylate transporter (MCT) homologues confirms the existence of a transporter family with an ancient past. Biochem J 329:321–328PubMedGoogle Scholar
  59. 59.
    Proud CG (2001) Regulation of mRNA translation. Essays Biochem 37:97–108PubMedGoogle Scholar
  60. 60.
    Py G, Eydoux N, PerezMartin A, Raynaud E, Brun JF, Prefaut C, Mercier J (2001) Streptozotocin-induced diabetes decreases rat sarcolemmal lactate transport. Metabolism 50:418–424CrossRefPubMedGoogle Scholar
  61. 61.
    Py G, Lambert K, Milhavet O, Eydoux N, Prefaut C, Mercier J (2002) Effects of streptozotocin-induced diabetes on markers of skeletal muscle metabolism and monocarboxylate transporter 1 to monocarboxylate transporter 4 transporters. Metabolism 51:807–813CrossRefPubMedGoogle Scholar
  62. 62.
    Rahman B, Schneider HP, Bröer A, Deitmer JW, Bröer S (1999) Helix 8 and helix 10 are involved in substrate recognition in the rat monocarboxylate transporter MCT1. Biochemistry 38:11577–11584PubMedGoogle Scholar
  63. 63.
    Rechsteiner M, Rogers SW (1996) PEST sequences and regulation by proteolysis. Trends Biochem Sci 21:267–271PubMedGoogle Scholar
  64. 64.
    Shewan AM, Marsh BJ, Melvin DR, Martin S, Gould GW, James DE (2000) The cytosolic C-terminus of the glucose transporter GLUT4 contains an acidic cluster endosomal targeting motif distal to the dileucine signal. Biochem J 350:99–107CrossRefPubMedGoogle Scholar
  65. 65.
    Utoguchi N, Audus KL (2000) Carrier-mediated transport of valproic acid in BeWo cells, a human trophoblast cell line. Int J Pharm 195:115–124CrossRefPubMedGoogle Scholar
  66. 66.
    Wilson MC, Jackson VN, Heddle C, Price NT, Pilegaard H, Juel C, Bonen A, Montgomery I, Hutter OF, Halestrap AP (1998) Lactic acid efflux from white skeletal muscle is catalyzed by the monocarboxylate transporter isoform MCT3. J Biol Chem 273:15920–15926PubMedGoogle Scholar
  67. 67.
    Wilson MC, Meredith D, Halestrap AP (2002) Fluorescence resonance energy transfer studies on the interaction between the lactate transporter MCT1 and CD147 provide information on the topology and stoichiometry of the complex in situ. J Biol Chem 277:3666–3672CrossRefPubMedGoogle Scholar
  68. 68.
    Wu XC, Whitfield LR, Stewart BH (2000) Atorvastatin transport in the Caco-2 cell model: contributions of P-glycoprotein and the proton-monocarboxylic acid co-transporter. Pharm Res 17:209–215CrossRefPubMedGoogle Scholar
  69. 69.
    Yoon HY, Philp NJ (1998) Genomic structure and developmental expression of the chicken monocarboxylate transporter MCT3. Exp Eye Res 67:417–424CrossRefPubMedGoogle Scholar
  70. 70.
    Yoon HY, Fanelli A, Grollman EF, Philp NJ (1997) Identification of a unique monocarboxylate transporter (MCT3) in retinal pigment epithelium. Biochem Biophys Res Commun 234:90–94CrossRefPubMedGoogle Scholar
  71. 71.
    Zeuthen T, Hamann S, LaCour M (1996) Cotransport of H+, lactate and H2O by membrane proteins in retinal pigment epithelium of bullfrog. J Physiol (Lond) 497:3–17Google Scholar
  72. 72.
    Zhao C, Wilson MC, Schuit F, Halestrap AP, Rutter GA (2001) Expression and distribution of lactate/monocarboxylate transporter isoforms in pancreatic islets and the exocrine pancreas. Diabetes 50:361–366PubMedGoogle Scholar

Copyright information

© Springer-Verlag  2004

Authors and Affiliations

  1. 1.Department of BiochemistryUniversity of BristolBristolUK
  2. 2.Department of Human Anatomy and GeneticsUniversity of OxfordOxfordUK

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