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Nonenzymatic Augmentation of Lactate Transport via Monocarboxylate Transporter Isoform 4 by Carbonic Anhydrase II

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Abstract

Monocarboxylate transporters (MCTs) are carriers of high-energy metabolites like lactate and pyruvate, and different MCT isoforms are expressed in a wide range of cells and tissues. Transport activity of MCT isoform 1 (MCT1), heterologously expressed in Xenopus oocytes, has previously been shown to be supported by carbonic anhydrase II (CAII) in a noncatalytic manner. In the present study, we investigated possible interactions of CAII with MCT4, expressed in Xenopus oocytes. MCT4 transport activity is enhanced both by injected and by coexpressed CAII, similar to MCT1, with the highest augmentation at low extracellular pH and low lactate concentrations. CAII-induced augmentation in MCT4 transport activity is independent from the enzyme’s catalytic function, as shown by application of the CA inhibitor ethoxyzolamide and by coexpression of MCT4 with the catalytically inactive mutant CAII-V143Y.

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References

  • Alexander RS, Nair SK, Christianson DW (1991) Engineering the hydrophobic pocket of carbonic anhydrase II. Biochemistry 30:11064–11072

    Article  CAS  PubMed  Google Scholar 

  • Alvarez BV, Vilas GL, Casey JR (2005) Metabolon disruption: a mechanism that regulates bicarbonate transport. EMBO J 24:2499–2511

    Article  CAS  PubMed  Google Scholar 

  • Becker HM, Deitmer JW (2004) Voltage dependence of H+ buffering mediated by sodium bicarbonate cotransport expressed in Xenopus oocytes. J Biol Chem 279:28057–28062

    Article  CAS  PubMed  Google Scholar 

  • Becker HM, Deitmer JW (2007) Carbonic anhydrase II increases the activity of the human electrogenic Na+/HCO3 − cotransporter. J Biol Chem 282:13508–13521

    Article  CAS  PubMed  Google Scholar 

  • Becker HM, Deitmer JW (2008) Nonenzymatic proton handling by carbonic anhydrase II during H+-lactate cotransport via monocarboxylate transporter 1. J Biol Chem 283:21655–21667

    Article  CAS  PubMed  Google Scholar 

  • Becker HM, Broer S, Deitmer JW (2004) Facilitated lactate transport by MCT1 when coexpressed with the sodium bicarbonate cotransporter (NBC) in Xenopus oocytes. Biophys J 86:235–247

    Article  CAS  PubMed  Google Scholar 

  • Becker HM, Fecher-Trost C, Hirnet D, Sültemeyer D, Deitmer JW (2005) Transport activity of MCT1 expressed in Xenopus oocytes is increased by interaction with carbonic anhydrase. J Biol Chem 280:39882–39889

    Article  CAS  PubMed  Google Scholar 

  • Bergersen LH (2007) Is lactate food for neurons? Comparison of monocarboxylate transporter subtypes in brain and muscle. Neuroscience 145:11–19

    Article  CAS  PubMed  Google Scholar 

  • Bevensee MO, Apkon M, Boron WF (1997) Intracellular pH regulation in cultured astrocytes from rat hippocampus. II. Electrogenic Na/HCO3 cotransport. J Gen Physiol 110:467–483

    Article  CAS  PubMed  Google Scholar 

  • Bishop D, Edge J, Thomas C, Mercier J (2007) High-intensity exercise acutely decreases the membrane content of MCT1 and MCT4 and buffer capacity in human skeletal muscle. J Appl Physiol 102:616–621

    Article  CAS  PubMed  Google Scholar 

  • Bröer S, Rahman B, Pellegri G, Pellerin L, Martin JL, Verleysdonk S, Hamprecht B, Magistretti PJ (1997) Comparison of lactate transport in astroglial cells and monocarboxylate transporter 1 (MCT 1) expressing Xenopus laevis oocytes. Expression of two different monocarboxylate transporters in astroglial cells and neurons. J Biol Chem 272:30096–30102

    Article  PubMed  Google Scholar 

  • 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 333:167–174

    PubMed  Google Scholar 

  • Brooks GA (1985) Lactate: glycolytic end product and oxidative substrate during sustained exercise in mammals—the “lactate shuttle”. In: Gilles R (ed) Comparative physiology and biochemistry: current topics and trends, vol A. Respiration—metabolism—circulation. Springer-Verlag, Berlin, pp 202–218

    Google Scholar 

  • Brown MA, Brooks GA (1994) Trans-stimulation of lactate transport from rat sarcolemmal membrane vesicles. Arch Biochem Biophys 313:22–28

    Article  CAS  PubMed  Google Scholar 

  • Deitmer JW (1991) Electrogenic sodium-dependent bicarbonate secretion by glial cells of the leech central nervous system. J Gen Physiol 98:637–655

    Article  CAS  PubMed  Google Scholar 

  • Deitmer JW (2002) A role for CO2 and bicarbonate transporters in metabolic exchanges in the brain. J Neurochem 80:721–726

    Article  CAS  PubMed  Google Scholar 

  • Deitmer JW, Szatkowski M (1990) Membrane potential dependence of intracellular pH regulation by identified glial cells in the leech central nervous system. J Physiol 421:617–631

    CAS  PubMed  Google Scholar 

  • Dimmer KS, Friedrich B, Lang F, Deitmer JW, Broer S (2000) The low-affinity monocarboxylate transporter MCT4 is adapted to the export of lactate in highly glycolytic cells. Biochem J 350:219–227

    Article  CAS  PubMed  Google Scholar 

  • Dubouchaud H, Butterfield GE, Wolfel EE, Bergman BC, Brooks GA (2000) Endurance training, expression, and physiology of LDH, MCT1, and MCT4 in human skeletal muscle. Am J Physiol 278:E571–E579

    CAS  Google Scholar 

  • Erlichman JS, Hewitt A, Damon TL, Hart M, Kurascz J, Li A, Leiter JC (2008) Inhibition of monocarboxylate transporter 2 in the retrotrapezoid nucleus in rats: a test of the astrocyte-neuron lactate-shuttle hypothesis. J Neurosci 28:4888–4896

    Article  CAS  PubMed  Google Scholar 

  • Fierke CA, Calderone TL, Krebs JF (1991) Functional consequences of engineering the hydrophobic pocket of carbonic anhydrase II. Biochemistry 30:11054–11063

    Article  CAS  PubMed  Google Scholar 

  • Gladden LB (2004) Lactate metabolism: a new paradigm for the third millennium. J Physiol 558:5–30

    Article  CAS  PubMed  Google Scholar 

  • Grichtchenko II, Chesler M (1994) Depolarization-induced acid secretion in gliotic hippocampal slices. Neuroscience 62:1057–1070

    Article  CAS  PubMed  Google Scholar 

  • Halestrap AP, Meredith D (2004) The SLC16 gene family—from monocarboxylate transporters (MCTs) to aromatic amino acid transporters and beyond. Pflugers Arch 447:619–628

    Article  CAS  PubMed  Google Scholar 

  • Halestrap AP, Price NT (1999) The proton-linked monocarboxylate transporter (MCT) family: structure, function and regulation. Biochem J 343:281–299

    Article  CAS  PubMed  Google Scholar 

  • Hashimoto T, Masuda S, Taguchi S, Brooks GA (2005) Immunohistochemical analysis of MCT1, MCT2 and MCT4 expression in rat plantaris muscle. J Physiol 567:121–129

    Article  CAS  PubMed  Google Scholar 

  • Hashimoto T, Hussien R, Cho HS, Kaufer D, Brooks GA (2008) Evidence for the mitochondrial lactate oxidation complex in rat neurons: demonstration of an essential component of brain lactate shuttles. PLoS One 3:e2915

    Article  PubMed  Google Scholar 

  • Ide K, Schmalbruch IK, Quistorff B, Horn A, Secher NH (2000) Lactate, glucose and O2 uptake in human brain during recovery from maximal exercise. J Physiol 522:159–164

    Article  CAS  PubMed  Google Scholar 

  • Jeffery S, Carter ND, Smith A (1986) Immunocytochemical localization of carbonic anhydrase isozymes I, II, and III in rat skeletal muscle. J Histochem Cytochem 34:513–516

    CAS  PubMed  Google Scholar 

  • Juel C (2001) Current aspects of lactate exchange: lactate/H+ transport in human skeletal muscle. Eur J Appl Physiol 86:12–16

    Article  CAS  PubMed  Google Scholar 

  • Juel C, Halestrap AP (1999) Lactate transport in skeletal muscle—role and regulation of the monocarboxylate transporter. J Physiol 517:633–642

    Article  CAS  PubMed  Google Scholar 

  • Juel C, Lundby C, Sander M, Calbet JA, Hall G (2003) Human skeletal muscle and erythrocyte proteins involved in acid-base homeostasis: adaptations to chronic hypoxia. J Physiol 548:639–648

    Article  CAS  PubMed  Google Scholar 

  • Li X, Alvarez BV, Casey JR, Reithmeier RA, Fliegel L (2002) Carbonic anhydrase II binds to and enhances activity of the Na+/H+ exchanger. J Biol Chem 277:36085–36091

    Article  CAS  PubMed  Google Scholar 

  • Li X, Liu Y, Alvarez BV, Casey JR, Fliegel L (2006) A novel carbonic anhydrase II binding site regulates NHE1 activity. Biochemistry 45:2414–2424

    Article  CAS  PubMed  Google Scholar 

  • Loiselle FB, Morgan PE, Alvarez BV, Casey JR (2004) Regulation of the human NBC3 Na+/HCO3 − cotransporter by carbonic anhydrase II and PKA. Am J Physiol 286:C1423–C1433

    Article  CAS  Google Scholar 

  • Lubow JM, Piñón IG, Avogaro A, Cobelli C, Treeson DM, Mandeville KA, Toffolo G, Boyle PJ (2006) Brain oxygen utilization is unchanged by hypoglycemia in normal humans: lactate, alanine, and leucine uptake are not sufficient to offset energy deficit. Am J Physiol 290:E149–E153

    CAS  Google Scholar 

  • Magistretti PJ, Pellerin L, Rothman DL, Shulman RG (1999) Energy on demand. Science 283:496–497

    Article  CAS  PubMed  Google Scholar 

  • 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 592:285–293

    Google Scholar 

  • McMurtrie HL, Cleary HJ, Alvarez BV, Loiselle FB, Sterling D, Morgan PE, Johnson DE, Casey JR (2004) The bicarbonate transport metabolon. J Enzyme Inhib Med Chem 19:231–236

    Article  CAS  PubMed  Google Scholar 

  • Messonnier L, Kristensen M, Juel C, Denis C (2007) Importance of pH regulation and lactate/H+ transport capacity for work production during supramaximal exercise in humans. J Appl Physiol 102:1936–1944

    Article  CAS  PubMed  Google Scholar 

  • Pellerin L, Halestrap AP, Pierre K (2005) Cellular and subcellular distribution of monocarboxylate transporters in cultured brain cells and in the adult brain. J Neurosci Res 79:55–64

    Article  CAS  PubMed  Google Scholar 

  • Pellerin L, Bouzier-Sore AK, Aubert A, Serres S, Merle M, Costalat R, Magistretti PJ (2007) Activity-dependent regulation of energy metabolism by astrocytes: an update. Glia 55:1251–1262

    Article  PubMed  Google Scholar 

  • Pushkin A, Abuladze N, Gross E, Newman D, Tatishchev S, Lee I, Fedotoff O, Bondar G, Azimov R, Ngyuen M, Kurtz I (2004) Molecular mechanism of kNBC1-carbonic anhydrase II interaction in proximal tubule cells. J Physiol 559:55–65

    Article  CAS  PubMed  Google Scholar 

  • Rafiki A, Boulland JL, Halestrap AP, Ottersen OP, Bergersen L (2003) Highly differential expression of the monocarboxylate transporters MCT2 and MCT4 in the developing rat brain. Neuroscience 122:677–688

    Article  CAS  PubMed  Google Scholar 

  • Richardson RS, Noyszewski EA, Leigh JS, Wagner PD (1998) Lactate efflux from exercising human skeletal muscle: role of intracellular PO2. J Appl Physiol 85:627–634

    CAS  PubMed  Google Scholar 

  • Ro HA, Carson JH (2004) pH microdomains in oligodentrocytes. J Biol Chem 279:37115–37123

    Article  CAS  PubMed  Google Scholar 

  • Tong CK, Cammer W, Chesler M (2000) Activity-dependent pH shifts in hippocampal slices from normal and carbonic anhydrase II-deficient mice. Glia 31:125–130

    Article  CAS  PubMed  Google Scholar 

  • van Hall G, Strømstad M, Rasmussen P, Jans O, Zaar M, Gam C, Quistorff B, Secher NH, Nielsen HB (2009) Blood lactate is an important energy source for the human brain. J Cereb Blood Flow Metab 29:1121–1129

    Article  PubMed  Google Scholar 

  • Vaughan-Jones RD, Peercy BE, Keener JP, Spitzer KW (2002) Intrinsic H+ ion mobility in the rabbit ventricular myocyte. J Physiol 541:139–158

    Article  CAS  PubMed  Google Scholar 

  • Vince JW, Reithmeier RA (1998) Carbonic anhydrase II binds to the carboxyl terminus of human band 3, the erythrocyte C1−/HCO3 − exchanger. J Biol Chem 273:28430–28437

    Article  CAS  PubMed  Google Scholar 

  • Vince JW, Reithmeier RA (2000) Identification of the carbonic anhydrase II binding site in the Cl−/HCO3 − anion exchanger AE1. Biochemistry 39:5527–5533

    Article  CAS  PubMed  Google Scholar 

  • Vince JW, Carlsson U, Reithmeier RA (2000) Localization of the Cl−/HCO3 − anion exchanger binding site to the amino-terminal region of carbonic anhydrase II. Biochemistry 39:13344–13349

    Article  CAS  PubMed  Google Scholar 

  • Walz W, Mukerji S (1988) Lactate production and release in cultured astrocytes. Neurosci Lett 86:296–300

    Article  CAS  PubMed  Google Scholar 

  • Westerblad H, Allen DG (1992) Changes of intracellular pH due to repetitive stimulation of single fibers from mouse skeletal muscle. J Physiol 449:49–71

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Dr. Stefan Bröer for providing the construct of MCT4. Furthermore, we thank Dr. Reinhart Reithmeier (Toronto, Canada) for providing wild-type CAII and Dr. Carol Fierke (Ann Arbor, MI) for the catalytically inactive mutant of CAII, CAII-V143Y. This study was supported by the Graduiertenkolleg 845 of the Deutsche Forschungsgemeinschaft and by the Landesschwerpunkt “Membrantransport.”

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  1. Arbeitsgruppe Zoologie/Membrantransport, FB Biologie, TU Kaiserslautern, P.O. Box 3049, 67653, Kaiserslautern, Germany

    Holger M. Becker

  2. Abteilung für Allgemeine Zoologie, FB Biologie, TU Kaiserslautern, P.O. Box 3049, 67653, Kaiserslautern, Germany

    Michael Klier & Joachim W. Deitmer

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  1. Holger M. Becker
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Correspondence to Holger M. Becker.

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Becker, H.M., Klier, M. & Deitmer, J.W. Nonenzymatic Augmentation of Lactate Transport via Monocarboxylate Transporter Isoform 4 by Carbonic Anhydrase II. J Membrane Biol 234, 125–135 (2010). https://doi.org/10.1007/s00232-010-9240-y

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  • DOI: https://doi.org/10.1007/s00232-010-9240-y

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