Skip to main content

Carbonic Anhydrases and Their Interplay with Acid/Base-Coupled Membrane Transporters

  • Chapter
  • First Online:
Carbonic Anhydrase: Mechanism, Regulation, Links to Disease, and Industrial Applications

Part of the book series: Subcellular Biochemistry ((SCBI,volume 75))

Abstract

Carbonic anhydrases (CAs) have not only been identified as ubiquitous enzymes catalyzing the fast reversible hydration of carbon dioxide to generate or consume protons and bicarbonate, but also as intra- and extracellular proteins, which facilitate transport function of many acid/base transporting membrane proteins, coined ‘transport metabolon’. Functional interaction between CAs and acid/base transporters, such as chloride/bicarbonate exchanger (AE), sodium-bicarbonate cotransporter (NBC) and sodium/hydrogen exchanger (NHE) has been shown to require both catalytic CA activity as well as direct binding of the enzyme to specific sites on the transporter. In contrast, functional interaction between different CA isoforms and lactate-proton-cotransporting monocarboxylate transporters (MCT) has been found to be isoform-specific and independent of CA catalytic activity, but seems to require an intramolecular proton shuttle within the enzyme. In this chapter, we review the various types of interactions between acid/base-coupled membrane carriers and different CA isoforms, as studied in vitro, in intact Xenopus oocytes, and in various mammalian cell types. Furthermore, we discuss recent findings that indicate the significance of these ‘transport metabolons’ for normal cell functions.

Susan C. Frost and Robert McKenna (eds.). Carbonic Anhydrase: Mechanism, Regulation, Links to Disease, and Industrial Applications

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Whitten ST, García-Moreno EB, Hilser VJ (2005) Local conformational fluctuations can modulate the coupling between proton binding and global structural transitions in proteins. Proc Natl Acad Sci U S A 102:4282–4287

    PubMed  CAS  Google Scholar 

  2. Hulikova A, Harris AL, Vaughan-Jones RD, Swietach P (2012) Acid-extrusion from tissue: the interplay between membrane transporters and pH buffers. Curr Pharm Des 18:1331–1337

    PubMed  CAS  Google Scholar 

  3. Srere P (1985) The metabolon. Trends Biochem Sci 14:313–314

    Google Scholar 

  4. Srere PA (1987) Complexes of sequential metabolic enzymes. Annu Rev Biochem 56:89–124

    PubMed  CAS  Google Scholar 

  5. Miles EW, Rhee S, Davies DR (1999) The molecular basis of substrate channeling. J Biol Chem 274:12193–12196

    PubMed  CAS  Google Scholar 

  6. Ovádi J (1991) Physiological significance of metabolic channelling. J Theor Biol 152:1–22

    PubMed  Google Scholar 

  7. Kifor G, Toon MR, Janoshazi A, Solomon AK (1993) Interaction between red cell membrane band 3 and cytosolic carbonic anhydrase. J Membr Biol 134:169–179

    PubMed  CAS  Google Scholar 

  8. Sterling D, Casey JR (2002) Bicarbonate transport proteins. Biochem Cell Biol 80:483–497

    PubMed  CAS  Google Scholar 

  9. Knauf PA, Breuer W, McCulloch L, Rothstein A (1978) N-(4-azido-2-nitrophenyl)-2-aminoethylsulfonate (NAP-taurine) as a photoaffinity probe for identifying membrane components containing the modifier site of the human red blood cell anion exchange system. J Gen Physiol 72:631–649

    PubMed  CAS  Google Scholar 

  10. Jennings ML (1989) Structure and function of the red blood cell anion transport protein. Annu Rev Biophys Biophys Chem 18:397–430

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  12. Vince JW, Reithmeier RA (2000) Identification of the carbonic anhydrase II binding site in the Cl(−)/HCO(3)(−) anion exchanger AE1. Biochemistry 39:5527–5533

    PubMed  CAS  Google Scholar 

  13. 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

    PubMed  CAS  Google Scholar 

  14. Casey JR, Pirraglia C, Reithmeier R (1992) Enzymatic deglycosylation of human band 3, the anion transport protein of the erythrocyte membrane. Effect on protein structure and transport properties. J Biol Chem 267:11940–11948

    PubMed  CAS  Google Scholar 

  15. Sterling D, Reithmeier RA, Casey JR (2001) A transport metabolon. Functional interaction of carbonic anhydrase II and chloride/bicarbonate exchangers. J Biol Chem 276:47886–47894

    PubMed  CAS  Google Scholar 

  16. Morgan PE, Pastoreková S, Stuart-Tilley AK, Alper SL, Casey JR (2007) Interactions of transmembrane carbonic anhydrase, CAIX, with bicarbonate transporters. Am J Physiol Cell Physiol 293:738–748

    Google Scholar 

  17. Dahl NK, Jiang L, Chernova MN, Stuart-Tilley AK, Shmukler BE, Alper SL (2003) Deficient HCO3 transport in an AE1 mutant with normal Cl- transport can be rescued by carbonic anhydrase II presented on an adjacent AE1 protomer. J Biol Chem 278:44949–44958

    PubMed  CAS  Google Scholar 

  18. Jennings ML (1984) Oligomeric structure and the anion transport function of human erythrocyte band 3 protein. J Membr Biol 80:105–117

    PubMed  CAS  Google Scholar 

  19. Scozzafava A, Supuran CT (2002) Carbonic anhydrase activators: human isozyme II is strongly activated by oligopeptides incorporating the carboxyterminal sequence of the bicarbonate anion exchanger AE1. Bioorg Med Chem Lett 12:1177–1180

    PubMed  CAS  Google Scholar 

  20. Kere J (2006) Overview of the SLC26 family and associated diseases. Novartis Found Symp 273:2–11

    PubMed  CAS  Google Scholar 

  21. Dorwart MR, Shcheynikov N, Wang Y, Stippec S, Muallem S (2007) SLC26A9 is a Cl(−) channel regulated by the WNK kinases. J Physiol 584:333–345

    PubMed  CAS  Google Scholar 

  22. Mount DB, Romero MF (2004) The SLC26 gene family of multifunctional anion exchangers. Pflügers Archiv Eur J Physiol 447:710–721

    CAS  Google Scholar 

  23. Casey JR, Grinstein S, Orlowski J (2010) Sensors and regulators of intracellular pH. Nat Rev Mol Cell Biol 11:50–61

    PubMed  CAS  Google Scholar 

  24. Ohana E, Shcheynikov N, Park M, Muallem S (2012) Solute carrier family 26 member a2 (Slc26a2) protein functions as an electroneutral SO4 2−/OH/Cl exchanger regulated by extracellular Cl. J Biol Chem 287:5122–5132

    PubMed  CAS  Google Scholar 

  25. Sterling D, Brown NJD, Supuran CT, Casey JR (2002) The functional and physical relationship between the DRA bicarbonate transporter and carbonic anhydrase II. Am J Physiol Cell Physiol 283:1522–1529

    Google Scholar 

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

    PubMed  CAS  Google Scholar 

  27. Soleimani M, Burnham CE (2001) Na+:HCO(3 ) cotransporters (NBC): cloning and characterization. J Membr Biol 183:71–84

    PubMed  CAS  Google Scholar 

  28. Romero MF, Fulton CM, Boron WF (2004) The SLC4 family of HCO3 transporters. Pflügers Archiv Eur J Physiol 447:495–509

    CAS  Google Scholar 

  29. Abuladze N, Lee I, Newman D (1998) Molecular cloning, chromosomal localization, tissue distribution, and functional expression of the human pancreatic sodium bicarbonate cotransporter. J Biol Chem 273:17689–17695

    PubMed  CAS  Google Scholar 

  30. Choi I, Romero MF, Khandoudi N, Bril A, Boron WF (1999) Cloning and characterization of a human electrogenic Na+-HCO 3 cotransporter isoform (hhNBC). Am J Physiol 276:576–584

    Google Scholar 

  31. Abuladze N, Song M, Pushkin A, Newman D, Lee I, Nicholas S, Kurtz I (2000) Structural organization of the human NBC1 gene: kNBC1 is transcribed from an alternative promoter in intron 3. Gene 251:109–122

    PubMed  CAS  Google Scholar 

  32. McAlear SD, Liu X, Williams JB, McNicholas-Bevensee CM, Bevensee MO (2006) Electrogenic Na/HCO3 cotransporter (NBCe1) variants expressed in Xenopus oocytes: functional comparison and roles of the amino and carboxy termini. J Gen Physiol 127:639–658

    PubMed  CAS  Google Scholar 

  33. Soleimani M, Grassi S, Aronson P (1987) Stoichiometry of Na+-HCO 3 cotransport in basolateral membrane vesicles isolated from rabbit renal cortex. J Clin Invest 79:1276–1280

    PubMed  CAS  Google Scholar 

  34. Deitmer JW, Schlue W (1989) An inwardly directed electrogenic sodium-bicarbonate co-transport in leech glial cells. J Physiol 411:179–194

    PubMed  CAS  Google Scholar 

  35. Bevensee MO, Weed RA, Boron WF (1997) Intracellular pH regulation in cultured astrocytes from rat hippocampus. I. Role of HCO3 . J Gen Physiol 110:453–465

    PubMed  CAS  Google Scholar 

  36. 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

    PubMed  CAS  Google Scholar 

  37. Aiello EA, Petroff MG, Mattiazzi AR, Cingolani HE (1998) Evidence for an electrogenic Na+-HCO3 symport in rat cardiac myocytes. J Physiol 512:137–148

    PubMed  CAS  Google Scholar 

  38. Gross E, Hawkins K, Abuladze N, Pushkin A, Cotton CU, Hopfer U, Kurtz I (2001) The stoichiometry of the electrogenic sodium bicarbonate cotransporter NBC1 is cell-type dependent. J Physiol 531:597–603

    PubMed  CAS  Google Scholar 

  39. Gross E, Hawkins K, Pushkin A, Sassani P, Dukkipati R, Abuladze N, Hopfer U, Kurtz I (2001) Phosphorylation of Ser(982) in the sodium bicarbonate cotransporter kNBC1 shifts the HCO(3)(−) : Na(+) stoichiometry from 3 : 1 to 2 : 1 in murine proximal tubule cells. J Physiol 537:659–665

    PubMed  CAS  Google Scholar 

  40. Gross E, Fedotoff O, Pushkin A, Abuladze N, Newman D, Kurtz I (2003) Phosphorylation-induced modulation of pNBC1 function: distinct roles for the amino- and carboxy-termini. J Physiol 549:673–682

    PubMed  CAS  Google Scholar 

  41. Ko SBH, Luo X, Hager H, Rojek A, Choi JY, Licht C, Suzuki M, Muallem S, Nielsen S, Ishibashi K (2002) AE4 is a DIDS-sensitive Cl(−)/HCO(−)(3) exchanger in the basolateral membrane of the renal CCD and the SMG duct. Am J Physiol Cell Physiol 283:1206–1218

    Google Scholar 

  42. Pushkin A, Kurtz I (2006) SLC4 base (HCO3 , CO3 2−) transporters: classification, function, structure, genetic diseases, and knockout models. Am J Physiol Renal Physiol 290:580–599

    Google Scholar 

  43. Alper SL (2009) Molecular physiology and genetics of Na+-independent SLC4 anion exchangers. J Exp Biol 212:1672–1683

    PubMed  CAS  Google Scholar 

  44. Burg M, Green N (1977) Bicarbonate transport by isolated perfused rabbit proximal convoluted tubules. Am J Physiol 233:307–314

    Google Scholar 

  45. Sasaki S, Marumo F (1989) Effects of carbonic anhydrase inhibitors on basolateral base transport of rabbit proximal straight tubule. Am J Physiol 257:947–952

    Google Scholar 

  46. Seki G, Frömter E (1992) Acetazolamide inhibition of basolateral base exit in rabbit renal proximal tubule S2 segment. Pflügers Archiv Eur J Physiol 422:60–65

    CAS  Google Scholar 

  47. Gross E, Pushkin A, Abuladze N, Fedotoff O, Kurtz I (2002) Regulation of the sodium bicarbonate cotransporter kNBC1 function: role of Asp986, Asp988 and kNBC1-carbonic anhydrase II binding. J Physiol 544:679–685

    PubMed  CAS  Google Scholar 

  48. 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

    PubMed  CAS  Google Scholar 

  49. Alvarez BV, Loiselle FB, Supuran CT, Schwartz GJ, Casey JR (2003) Direct extracellular interaction between carbonic anhydrase IV and the human NBC1 sodium/bicarbonate co-transporter. Biochemistry 42:12321–12329

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  51. Schueler C, Becker HM, McKenna R, Deitmer JW (2011) Transport activity of the sodium bicarbonate cotransporter NBCe1 is enhanced by different isoforms of carbonic anhydrase. PLoS One 6:e27167

    PubMed  CAS  Google Scholar 

  52. 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 Cell Physiol 286:1423–1433

    Google Scholar 

  53. Ro H, Carson JH (2004) pH microdomains in oligodendrocytes. J Biol Chem 279:37115–37123

    PubMed  CAS  Google Scholar 

  54. Boussouf A, Lambert R, Gaillard S (1997) Voltage-dependent Na+/HCO3 cotransporter and Na+/H+ exchanger are involved in intracellular pH regulation of cultured mature rat cerebellar oligodendrocytes. Glia 19:74–84

    PubMed  CAS  Google Scholar 

  55. Boussouf A, Gaillard S (2000) Intracellular pH changes during oligodendrocyte differentiation in primary culture. J Neurosci Res 59:731–739

    PubMed  CAS  Google Scholar 

  56. Sterling D, Alvarez BV, Casey JR (2002) The extracellular component of a transport metabolon. Extracellular loop 4 of the human AE1 Cl/HCO3 exchanger binds carbonic anhydrase IV. J Biol Chem 277:25239–25246

    PubMed  CAS  Google Scholar 

  57. Tang XB, Fujinaga J, Kopito R, Casey JR (1998) Topology of the region surrounding Glu681 of human AE1 protein, the erythrocyte anion exchanger. J Biol Chem 273:22545–22553

    PubMed  CAS  Google Scholar 

  58. Casey JR, Sly WS, Shah GN, Alvarez BV (2009) Bicarbonate homeostasis in excitable tissues: role of AE3 Cl/HCO3 exchanger and carbonic anhydrase XIV interaction. Am J Physiol Cell Physiol 297:1091–1102

    Google Scholar 

  59. Svichar N, Waheed A, Sly WS, Hennings JC, Hübner CA, Chesler M (2009) Carbonic anhydrases CA4 and CA14 both enhance AE3-mediated Cl-HCO3− exchange in hippocampal neurons. J Neurosci 29:3252–3258

    PubMed  CAS  Google Scholar 

  60. Orlowski A, De Giusti VC, Morgan PE, Aiello EA, Alvarez BV (2012) Binding of carbonic anhydrase IX to extracellular loop 4 of the NBCe1 Na+/HCO3 cotransporter enhances NBCe1-mediated HCO3 influx in the rat heart. Am J Physiol Cell Physiol 303:69–80

    Google Scholar 

  61. Svastova E, Witarski W, Csaderova L, Kosik I, Skvarkova L, Hulikova A, Zatovicova M, Barathova M, Kopacek J, Pastorek J, Pastorekova S (2012) Carbonic anhydrase IX interacts with bicarbonate transporters in lamellipodia and increases cell migration via its catalytic domain. J Biol Chem 287:3392–33402

    PubMed  CAS  Google Scholar 

  62. Stock C, Schwab A (2009) Protons make tumor cells move like clockwork. Pflügers Archiv Eur J Physiol 458:981–992

    CAS  Google Scholar 

  63. Lu J, Daly CM, Parker MD, Gill HS, Piermarini PM, Pelletier MF, Boron WF (2006) Effect of human carbonic anhydrase II on the activity of the human electrogenic Na/HCO3 cotransporter NBCe1-A in Xenopus oocytes. J Biol Chem 281:19241–19250

    PubMed  CAS  Google Scholar 

  64. Yamada H, Horita S, Suzuki M, Fujita T, Seki G (2011) Functional role of a putative carbonic anhydrase II-binding domain in the electrogenic Na+-HCO3 cotransporter NBCe1 expressed in Xenopus oocytes. Channels 5:106–109

    PubMed  CAS  Google Scholar 

  65. Piermarini PM, Kim EY, Boron WF (2007) Evidence against a direct interaction between intracellular carbonic anhydrase II and pure C-terminal domains of SLC4 bicarbonate transporters. J Biol Chem 282:1409–1421

    PubMed  CAS  Google Scholar 

  66. Malo ME, Fliegel L (2006) Physiological role and regulation of the Na+/H+ exchanger. Can J Physiol Pharmacol 84:1081–1095

    PubMed  CAS  Google Scholar 

  67. Slepkov ER, Rainey JK, Sykes BD, Fliegel L (2007) Structural and functional analysis of the Na+/H+ exchanger. Biochem J 401:623–633

    PubMed  CAS  Google Scholar 

  68. Fliegel L (2009) Regulation of the Na(+)/H(+) exchanger in the healthy and diseased myocardium. Expert Opin Ther Targets 13:55–68

    PubMed  CAS  Google Scholar 

  69. Ohgaki R, Van IJzendoorn SCD, Matsushita M, Hoekstra D, Kanazawa H (2011) Organellar Na+/H+ exchangers: novel players in organelle pH regulation and their emerging functions. Biochemistry 50:443–450

    PubMed  CAS  Google Scholar 

  70. Orlowski J, Grinstein S (2004) Diversity of the mammalian sodium/proton exchanger SLC9 gene family. Pflügers Archiv Eur J Physiol 447:549–565

    CAS  Google Scholar 

  71. Fliegel L, Dyck JR, Wang H, Fong C, Haworth RS (1993) Cloning and analysis of the human myocardial Na+/H+ exchanger. Mol Cell Biochem 125:137–143

    PubMed  CAS  Google Scholar 

  72. Fliegel L, Sardet C, Pouyssegur J, Barr A (1991) Identification of the protein and cDNA of the cardiac Na+/H+ exchanger. FEBS Lett 279:25–29

    PubMed  CAS  Google Scholar 

  73. Kemp G, Young H, Fliegel L (2008) Structure and function of the human Na+/H+ exchanger isoform 1. Channels 2:329–336

    PubMed  Google Scholar 

  74. Pedersen SF, O’Donnell ME, Anderson SE, Cala PM (2006) Physiology and pathophysiology of Na+/H+ exchange and Na+ -K+ -2Cl cotransport in the heart, brain, and blood. Am J Physiol Regul Integr Comp Physiol 291:1–25

    Google Scholar 

  75. Karmazyn M, Moffat MP (1993) Role of Na+/H+ exchange in cardiac physiology and pathophysiology: mediation of myocardial reperfusion injury by the pH paradox. Cardiovasc Res 27:915–924

    PubMed  CAS  Google Scholar 

  76. Wallert MA, Fröhlich O (1989) Na+-H+ exchange in isolated myocytes from adult rat heart. Am J Physiol 257:207–213

    Google Scholar 

  77. Denker SP, Huang DC, Orlowski J, Furthmayr H, Barber DL (2000) Direct binding of the Na–H exchanger NHE1 to ERM proteins regulates the cortical cytoskeleton and cell shape independently of H(+) translocation. Mol Cell 6:1425–1436

    PubMed  CAS  Google Scholar 

  78. Avkiran M, Marber MS (2002) Na(+)/H(+) exchange inhibitors for cardioprotective therapy: progress, problems and prospects. J Am Coll Cardiol 39:747–753

    PubMed  CAS  Google Scholar 

  79. Cardone RA, Casavola V, Reshkin SJ (2005) The role of disturbed pH dynamics and the Na+/H+ exchanger in metastasis. Nat Rev Cancer 5:786–795

    PubMed  CAS  Google Scholar 

  80. Wu Q, Pierce WM, Delamere NA (1998) Cytoplasmic pH responses to carbonic anhydrase inhibitors in cultured rabbit nonpigmented ciliary epithelium. J Membr Biol 162:31–38

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  82. 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

    PubMed  CAS  Google Scholar 

  83. Weise A, Becker HM, Deitmer JW (2007) Enzymatic suppression of the membrane conductance associated with the glutamine transporter SNAT3 expressed in Xenopus oocytes by carbonic anhydrase II. J Gen Physiol 130:203–215

    PubMed  CAS  Google Scholar 

  84. Weise A, Schneider H, McKenna R, Deitmer JW (2011) Substrate-dependent interference of carbonic anhydrases with the glutamine transporter SNAT3-induced conductance. Cell Physiol Biochem 27:79–90

    PubMed  CAS  Google Scholar 

  85. 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 304:751–760

    PubMed  CAS  Google Scholar 

  86. 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

    PubMed  Google Scholar 

  87. Bröer S, Schneider HP, Bröer A, Deitmer JW (1998) Characterization of the monocarboxylate transporter 1 expressed in Xenopus laevis oocytes by changes in cytosolic pH. Biochem J 174:167–174

    Google Scholar 

  88. 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 270:1843–1849

    PubMed  CAS  Google Scholar 

  89. 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 324:447–453

    PubMed  CAS  Google Scholar 

  90. Bröer S, Bröer A, Schneider HP, Stegen C, Halestrap AP, Deitmer JW (1999) Characterization of the high-affinity monocarboxylate transporter MCT2 in Xenopus laevis oocytes. Biochem J 535:529–535

    Google Scholar 

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

    PubMed  CAS  Google Scholar 

  92. Pellerin L, Pellegri G, Bittar PG, Charnay Y, Bouras C, Martin JL, Stella N, Magistretti PJ (1998) Evidence supporting the existence of an activity-dependent astrocyte-neuron lactate shuttle. Dev Neurosci 20:291–299

    PubMed  CAS  Google Scholar 

  93. Bergersen L, Wærhaug 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 δ-glutamate receptors in postsynaptic densities of parallel fiber-Purkinje cell synapses. Exp Brain Res 136:523–534

    PubMed  CAS  Google Scholar 

  94. Pierre K, Pellerin L (2005) Monocarboxylate transporters in the central nervous system: distribution, regulation and function. J Neurochem 94:1–14

    PubMed  CAS  Google Scholar 

  95. Yoon H, Fanelli A, Grollman EF, Philp NJ (1997) Identification of a unique monocarboxylate transporter (MCT3) in retinal pigment epithelium. Biochem Biophys Res Commun 234:90–94

    PubMed  CAS  Google Scholar 

  96. Philp NJ, Yoon H, Lombardi L (2001) Mouse MCT3 gene is expressed preferentially in retinal pigment and choroid plexus epithelia. Am J Physiol Cell Physiol 280:1319–1326

    Google Scholar 

  97. 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 39:9351–9357

    PubMed  CAS  Google Scholar 

  98. 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 350:219–227

    PubMed  CAS  Google Scholar 

  99. 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 273:15920–15926

    PubMed  CAS  Google Scholar 

  100. Pinheiro C, Reis RM, Ricardo S, Longatto-Filho A, Schmitt F, Baltazar F (2010) Expression of monocarboxylate transporters 1, 2, and 4 in human tumours and their association with CD147 and CD44. J Biomed Biotechnol 2010:427694

    PubMed  Google Scholar 

  101. Halestrap AP, Wilson MC (2012) The monocarboxylate transporter family–role and regulation. IUBMB Life 64:109–119

    PubMed  CAS  Google Scholar 

  102. Pinheiro C, Longatto-Filho A, Azevedo-Silva J, Casal M, Schmitt FC, Baltazar F (2012) Role of monocarboxylate transporters in human cancers: state of the art. J Bioenerg Biomembr 44:127–139

    PubMed  CAS  Google Scholar 

  103. Halestrap AP (2012) The monocarboxylate transporter family–structure and functional characterization. IUBMB Life 64:1–9

    PubMed  CAS  Google Scholar 

  104. Wilson MC, Meredith D, Fox JEM, Manoharan C, Davies AJ, Halestrap AP (2005) Basigin (CD147) is the target for organomercurial inhibition of monocarboxylate transporter isoforms 1 and 4: the ancillary protein for the insensitive MCT2 is EMBIGIN (gp70). J Biol Chem 280:27213–27221

    PubMed  CAS  Google Scholar 

  105. Wilson MC, Meredith D, Bunnun C, Sessions RB, Halestrap AP (2009) Studies on the DIDS-binding site of monocarboxylate transporter 1 suggest a homology model of the open conformation and a plausible translocation cycle. J Biol Chem 284:20011–20021

    PubMed  CAS  Google Scholar 

  106. Wetzel P, Hasse A, Papadopoulos S, Voipio J, Kaila K, Gros G (2001) Extracellular carbonic anhydrase activity facilitates lactic acid transport in rat skeletal muscle fibres. J Physiol 531:743–756

    PubMed  CAS  Google Scholar 

  107. Hallerdei J, Scheibe RJ, Parkkila S, Waheed A, Sly WS, Gros G, Wetzel P, Endeward V (2010) T tubules and surface membranes provide equally effective pathways of carbonic anhydrase-facilitated lactic acid transport in skeletal muscle. PLoS One 5:e15137

    PubMed  CAS  Google Scholar 

  108. Scheibe RJ, Mundhenk K, Becker T, Hallerdei J, Waheed A, Shah GN, Sly WS, Gros G, Wetzel P (2008) Carbonic anhydrases IV and IX: subcellular localization and functional role in mouse skeletal muscle. Am J Physiol Cell Physiol 294:402–412

    Google Scholar 

  109. Scheibe RJ, Gros G, Parkkila S, Waheed A, Grubb JH, Shah GN, Sly WS, Wetzel P (2006) Expression of membrane-bound carbonic anhydrases IV, IX, and XIV in the mouse heart. J Histochem Cytochem 54:1379–1391

    PubMed  CAS  Google Scholar 

  110. Svichar N, Chesler M (2003) Surface carbonic anhydrase activity on astrocytes and neurons facilitates lactate transport. Glia 41:415–419

    PubMed  Google Scholar 

  111. Svichar N, Esquenazi S, Waheed A, Sly WS, Chesler M (2006) Functional demonstration of surface carbonic anhydrase IV activity on rat astrocytes. Glia 53:241–247

    PubMed  Google Scholar 

  112. Becker HM, Hirnet D, Fecher-Trost C, 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

    PubMed  CAS  Google Scholar 

  113. 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

    PubMed  CAS  Google Scholar 

  114. Becker HM, Klier M, Deitmer JW (2010) Nonenzymatic augmentation of lactate transport via monocarboxylate transporter isoform 4 by carbonic anhydrase II. J Membr Biol 234:125–135

    PubMed  CAS  Google Scholar 

  115. Klier M, Schüler C, Halestrap AP, Sly WS, Deitmer JW, Becker HM (2011) Transport activity of the high-affinity monocarboxylate transporter MCT2 is enhanced by extracellular carbonic anhydrase IV but not by intracellular carbonic anhydrase II. J Biol Chem 286:27781–27791

    PubMed  CAS  Google Scholar 

  116. Stridh MH, Alt MD, Wittmann S, Heidtmann H, Aggarwal M, Riederer B, Seidler U, Wennemuth G, McKenna R, Deitmer JW, Becker HM (2012) Lactate flux in astrocytes is enhanced by a non-catalytic action of carbonic anhydrase II. J Physiol 590:2333–2351

    PubMed  CAS  Google Scholar 

  117. Almquist J, Lang P, Prätzel-Wolters D, Deitmer JW, Jirstrand M, Becker HM (2010) A Kinetic Model of the Monocarboxylate Transporter MCT1 and its Interaction with Carbonic Anhydrase II. J Comput Sci Syst Biol 3:107–116

    CAS  Google Scholar 

  118. Fisher SZ, Maupin CM, Budayova-Spano M, Govindasamy L, Tu C, Agbandje-McKenna M, Silverman DN, Voth GA, McKenna R (2007) Atomic crystal and molecular dynamics simulation structures of human carbonic anhydrase II: insights into the proton transfer mechanism. Biochemistry 46:2930–2937

    PubMed  CAS  Google Scholar 

  119. Becker HM, Klier M, Schüler C, McKenna R, Deitmer JW (2011) Intramolecular proton shuttle supports not only catalytic but also noncatalytic function of carbonic anhydrase II. Proc Natl Acad Sci U S A 108:3071–3076

    PubMed  CAS  Google Scholar 

  120. Duda D, Tu C, Qian M, Laipis P, Agbandje-McKenna M, Silverman DN, McKenna R (2001) Structural and kinetic analysis of the chemical rescue of the proton transfer function of carbonic anhydrase II. Biochemistry 40:1741–1748

    PubMed  CAS  Google Scholar 

  121. Martínez C, Kalise D, Barros LF (2010) General requirement for harvesting antennae at ca and h channels and transporters. Front Neuroenerg 2:1–8

    Google Scholar 

  122. Ovens MJ, Davies AJ, Wilson MC, Murray CM, Halestrap AP (2010) AR-C155858 is a potent inhibitor of monocarboxylate transporters MCT1 and MCT2 that binds to an intracellular site involving transmembrane helices 7–10. Biochem J 425:523–530

    PubMed  CAS  Google Scholar 

  123. Gutman M, Nachliel E, Friedman R (2006) The dynamics of proton transfer between adjacent sites. Photochem Photobiol Sci 5:531–537

    PubMed  CAS  Google Scholar 

  124. Adelroth P, Brzezinski P (2004) Surface-mediated proton-transfer reactions in membrane-bound proteins. Biochim Biophys Acta 1655:102–115

    PubMed  CAS  Google Scholar 

  125. Brändén M, Sandén T, Brzezinski P, Widengren J (2006) Localized proton microcircuits at the biological membrane-water interface. Proc Natl Acad Sci U S A 103:19766–19770

    PubMed  Google Scholar 

  126. Zampighi GA, Kreman M, Boorer KJ, Loo DD, Bezanilla F, Chandy G, Hall JE, Wright EM (1995) A method for determining the unitary functional capacity of cloned channels and transporters expressed in Xenopus laevis oocytes. J Membr Biol 148:65–78

    PubMed  CAS  Google Scholar 

  127. Alvarez L, Fanjul M, Carter N, Hollande E (2001) Carbonic anhydrase II associated with plasma membrane in a human pancreatic duct cell line (CAPAN-1). J Histochem Cytochem 49:1045–1053

    PubMed  CAS  Google Scholar 

  128. Hurt JD, Tu C, Laipis PJ, Silverman DN (1997) Catalytic properties of murine carbonic anhydrase IV. J Biol Chem 272:13512–13518

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Holger M. Becker .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Science+Business Media Dordrecht

About this chapter

Cite this chapter

Becker, H.M., Klier, M., Deitmer, J.W. (2014). Carbonic Anhydrases and Their Interplay with Acid/Base-Coupled Membrane Transporters. In: Frost, S., McKenna, R. (eds) Carbonic Anhydrase: Mechanism, Regulation, Links to Disease, and Industrial Applications. Subcellular Biochemistry, vol 75. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-7359-2_7

Download citation

Publish with us

Policies and ethics