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The molecular mechanism of SLC34 proteins: insights from two decades of transport assays and structure-function studies

  • Ian C. ForsterEmail author
Invited Review

Abstract

The expression cloning some 25 years ago of the first member of SLC34 solute carrier family, the renal sodium-coupled inorganic phosphate cotransporter (NaPi-IIa) from rat and human tissue, heralded a new era of research into renal phosphate handling by focussing on the carrier proteins that mediate phosphate transport. The cloning of NaPi-IIa was followed by that of the intestinal NaPi-IIb and renal NaPi-IIc isoforms. These three proteins constitute the main secondary-active Na+-driven pathways for apical entry of inorganic phosphate (Pi) across renal and intestinal epithelial, as well as other epithelial-like organs. The key role these proteins play in mammalian Pi homeostasis was revealed in the intervening decades by numerous in vitro and animal studies, including the development of knockout animals for each gene and the detection of naturally occurring mutations that can lead to Pi-handling dysfunction in humans. In addition to characterising their physiological regulation, research has also focused on understanding the underlying transport mechanism and identifying structure-function relationships. Over the past two decades, this research effort has used real-time electrophysiological and fluorometric assays together with novel computational biology strategies to develop a detailed, but still incomplete, understanding of the transport mechanism of SLC34 proteins at the molecular level. This review will focus on how our present understanding of their molecular mechanism has evolved in this period by highlighting the key experimental findings.

Keywords

Phosphate cotransport Electrophysiology Fluorometry Kinetics Structure-function 

Notes

Acknowledgements

The author wishes to acknowledge the numerous contributions made by those working in the phosphate transport field past and present. The support and encouragement given by Heini Murer and Jürg Biber (University of Zurich), Ernest Wright and his past and present colleagues Don Loo, Bruce Hirayama and Sepehr Eskandari (UCLA) and more recently the collaborations with Cristina Fenollar-Ferrer and Lucy Forrest (NIH) are particularly appreciated. Special thanks are due to colleagues, postdocs and doctoral candidates at the Murer laboratory, without whom the insights gained over the years would have been impossible, and whose names and contributions appear in the original references. Most of the studies reported here were supported by grants from the Swiss National Science Foundation and Hartmann Müller-Stiftung (University of Zurich) to the author and Heini Murer, as well as other funding sources cited in the original publications. Finally, the author acknowledges the outstanding support from Steven Petrou and colleagues at the Ion Channels in Human Diseases Laboratory (Florey Institute).

References

  1. 1.
    Abramson J, Smirnova I, Kasho V, Verner G, Iwata S, Kaback HR (2003) The lactose permease of Escherichia coli: overall structure, the sugar-binding site and the alternating access model for transport. FEBS Lett 555:96–101PubMedCrossRefGoogle Scholar
  2. 2.
    Andrini O, Ghezzi C, Murer H, Forster IC (2008) The leak mode of type II Na(+)-P(i) cotransporters. Channels (Austin) 2:346–357CrossRefGoogle Scholar
  3. 3.
    Andrini O, Meinild AK, Ghezzi C, Murer H, Forster IC (2012) Lithium interactions with Na+−coupled inorganic phosphate cotransporters: insights into the mechanism of sequential cation binding. Am J Phys Cell Physiol 302:C539–C554CrossRefGoogle Scholar
  4. 4.
    Armstrong CM, Bezanilla F (1974) Charge movement associated with the opening and closing of the activation gates of the Na channels. J Gen Physiol 63:533–552PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Bacconi A, Ravera S, Virkki LV, Murer H, Forster IC (2007) Temperature dependence of steady-state and presteady-state kinetics of a type IIb Na+/P i cotransporter. J Membr Biol 215:81–92.  https://doi.org/10.1007/s00232-007-9008-1 PubMedCrossRefGoogle Scholar
  6. 6.
    Bacconi A, Virkki LV, Biber J, Murer H, Forster IC (2005) Renouncing electrogenicity is not free of charge: switching on electrogenicity in a Na+-coupled phosphate cotransporter. Proc Natl Acad Sci U S A 102:12606–12611PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Bazzone A, Barthmes M, Fendler K (2017) SSM-based electrophysiology for transporter research. Methods Enzymol 594:31–83.  https://doi.org/10.1016/bs.mie.2017.05.008 PubMedCrossRefGoogle Scholar
  8. 8.
    Bezanilla F (2008) How membrane proteins sense voltage. Nat Rev Mol Cell Biol 9:323–332PubMedCrossRefGoogle Scholar
  9. 9.
    Bezanilla F (2018) Gating currents. J Gen Physiol 150:911–932.  https://doi.org/10.1085/jgp.201812090 PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Biber J, Custer M, Magagnin S, Hayes G, Werner A, Lotscher M, Kaissling B, Murer H (1996) Renal Na/Pi-cotransporters. Kidney Int 49:981–985PubMedCrossRefGoogle Scholar
  11. 11.
    Biber J, Hernando N, Forster I (2013) Phosphate transporters and their function. Annu Rev Physiol 75:535–550.  https://doi.org/10.1146/annurev-physiol-030212-183748 PubMedCrossRefGoogle Scholar
  12. 12.
    Boyer CJ, Xiao Y, Dugre A, Vincent E, Delisle MC, Beliveau R (1996) Phosphate deprivation induces overexpression of two proteins related to the rat renal phosphate cotransporter NaPi-2. Biochim Biophys Acta 1281:117–123PubMedCrossRefGoogle Scholar
  13. 13.
    Burckhardt G, Stern H, Murer H (1981) The influence of pH on phosphate transport into rat renal brush border membrane vesicles. Pflugers Arch 390:191–197PubMedCrossRefGoogle Scholar
  14. 14.
    Busch A, Waldegger S, Herzer T, Biber J, Markovich D, Hayes G, Murer H, Lang F (1994) Electrophysiological analysis of Na+/Pi cotransport mediated by a transporter cloned from rat kidney and expressed in Xenopus oocytes. Proc Natl Acad Sci U S A 91:8205–8208PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Busch AE, Wagner CA, Schuster A, Waldegger S, Biber J, Murer H, Lang F (1995) Properties of electrogenic Pi transport by a human renal brush border Na+/Pi transporter. J Am Soc Nephrol 6:1547–1551PubMedGoogle Scholar
  16. 16.
    Cha A, Bezanilla F (1998) Structural implications of fluorescence quenching in the Shaker K+ channel. J Gen Physiol 112:391–408PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Cha A, Zerangue N, Kavanaugh M, Bezanilla F (1998) Fluorescence techniques for studying cloned channels and transporters expressed in Xenopus oocytes. Methods Enzymol 296:566–578PubMedCrossRefGoogle Scholar
  18. 18.
    Chen XZ, Coady MJ, Jackson F, Berteloot A, Lapointe JY (1995) Thermodynamic determination of the Na+: glucose coupling ratio for the human SGLT1 cotransporter. Biophys J 69:2405–2414.  https://doi.org/10.1016/S0006-3495(95)80110-4 PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Cheng L, Sacktor B (1981) Sodium gradient-dependent phosphate transport in renal brush border membrane vesicles. J Biol Chem 256:1556–1564PubMedGoogle Scholar
  20. 20.
    de la Horra C, Hernando N, Forster I, Biber J, Murer H (2001) Amino acids involved in sodium interaction of murine type II Na+-Pi cotransporters expressed in Xenopus oocytes. J Physiol 531:383–391PubMedCentralCrossRefGoogle Scholar
  21. 21.
    de la Horra C, Hernando N, Lambert G, Forster I, Biber J, Murer H (2000) Molecular determinants of pH sensitivity of the type IIa Na/Pi cotransporter. J Biol Chem 275:6284–6287PubMedCrossRefGoogle Scholar
  22. 22.
    Dinour D, Davidovits M, Ganon L, Ruminska J, Forster IC, Hernando N, Eyal E, Holtzman EJ, Wagner CA (2016) Loss of function of NaPiIIa causes nephrocalcinosis and possibly kidney insufficiency. Pediatr Nephrol 31:2289–2297.  https://doi.org/10.1007/s00467-016-3443-0 PubMedCrossRefGoogle Scholar
  23. 23.
    Drew D, Boudker O (2016) Shared molecular mechanisms of membrane transporters. Annu Rev Biochem 85:543–572.  https://doi.org/10.1146/annurev-biochem-060815-014520 PubMedCrossRefGoogle Scholar
  24. 24.
    Ehnes C, Forster IC, Bacconi A, Kohler K, Biber J, Murer H (2004) Structure-function relations of the first and fourth extracellular linkers of the type IIa Na+/Pi cotransporter: II. Substrate interaction and voltage dependency of two functionally important sites. J Gen Physiol 124:489–503PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Ehnes C, Forster IC, Kohler K, Bacconi A, Stange G, Biber J, Murer H (2004) Structure-function relations of the first and fourth predicted extracellular linkers of the type IIa Na+/Pi cotransporter: I. Cysteine scanning mutagenesis. J Gen Physiol 124:475–488PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Ehnes C, Forster IC, Kohler K, Biber J, Murer H (2002) Functional studies on a split type II Na/Pi-cotransporter. J Membr Biol 188:227–236PubMedCrossRefGoogle Scholar
  27. 27.
    Eskandari S (2009) Remarkable commonalities of electrogenic and electroneutral Na+-phosphate cotransporters. J Physiol 587:4131–4132.  https://doi.org/10.1113/jphysiol.2009.179119 PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Faham S, Watanabe A, Besserer GM, Cascio D, Specht A, Hirayama BA, Wright EM, Abramson J (2008) The crystal structure of a sodium galactose transporter reveals mechanistic insights into Na+/sugar symport. Science 321:810–814PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Fenollar-Ferrer C, Forster IC, Patti M, Knoepfel T, Werner A, Forrest LR (2015) Identification of the first sodium binding site of the phosphate cotransporter NaPi-IIa (SLC34A1). Biophys J 108:2465–2480.  https://doi.org/10.1016/j.bpj.2015.03.054 PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Fenollar-Ferrer C, Patti M, Knopfel T, Werner A, Forster IC, Forrest LR (2014) Structural fold and binding sites of the human Na(+)-phosphate cotransporter NaPi-II. Biophys J 106:1268–1279.  https://doi.org/10.1016/j.bpj.2014.01.043 PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Fitzgerald GA, Mulligan C, Mindell JA (2017) A general method for determining secondary active transporter substrate stoichiometry. Elife 6.  https://doi.org/10.7554/eLife.21016
  32. 32.
    Forster I, Biber J, Murer H (1999) Electrophysiological analysis of renal Na+-coupled divalent anion transporters. Pharm Biotechnol 12:251–267PubMedCrossRefGoogle Scholar
  33. 33.
    Forster I, Hernando N, Biber J, Murer H (1998) The voltage dependence of a cloned mammalian renal type II Na+/Pi cotransporter (NaPi-2). J Gen Physiol 112:1–18PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Forster IC, Biber J, Murer H (2000) Proton-sensitive transitions of renal type II Na(+)-coupled phosphate cotransporter kinetics. Biophys J 79:215–230.  https://doi.org/10.1016/S0006-3495(00)76285-0 PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Forster IC, Hernando N, Biber J, Murer H (2006) Proximal tubular handling of phosphate: a molecular perspective. Kidney Int 70:1548–1559PubMedCrossRefGoogle Scholar
  36. 36.
    Forster IC, Hernando N, Biber J, Murer H (2012) Phosphate transport kinetics and structure-function relationships of SLC34 and SLC20 proteins. Curr Top Membr 70:313–356PubMedCrossRefGoogle Scholar
  37. 37.
    Forster IC, Hernando N, Biber J, Murer H (2013) Phosphate transporters of the SLC20 and SLC34 families. Mol Asp Med 34:386–395CrossRefGoogle Scholar
  38. 38.
    Forster IC, Kohler K, Biber J, Murer H (2002) Forging the link between structure and function of electrogenic cotransporters: the renal type IIa Na+/Pi cotransporter as a case study. Prog Biophys Mol Biol 80:69–108PubMedCrossRefGoogle Scholar
  39. 39.
    Forster IC, Kohler K, Stange G, Biber J, Murer H (2002) Modulation of renal type IIa Na+/Pi cotransporter kinetics by the arginine modifier phenylglyoxal. J Membr Biol 187:85–96PubMedCrossRefGoogle Scholar
  40. 40.
    Forster IC, Loo DD, Eskandari S (1999) Stoichiometry and Na+ binding cooperativity of rat and flounder renal type II Na+-Pi cotransporters. Am J Phys 276:F644–F649Google Scholar
  41. 41.
    Forster IC, Virkki LV, Bossi E, Murer H, Biber J (2006) Electrogenic kinetics of a mammalian intestinal Na+/Pi-cotransporter. J Membr Biol 212:177–190PubMedCrossRefGoogle Scholar
  42. 42.
    Forster IC, Wagner CA, Busch AE, Lang F, Biber J, Hernando N, Murer H, Werner A (1997) Electrophysiological characterization of the flounder type II Na+/Pi cotransporter (NaPi-5) expressed in Xenopus laevis oocytes. J Membr Biol 160:9–25PubMedCrossRefGoogle Scholar
  43. 43.
    Fromter E (1979) The Feldberg lecture 1976. Solute transport across epithelia: what can we learn from micropuncture studies in kidney tubules? J Physiol 288:1–31PubMedPubMedCentralGoogle Scholar
  44. 44.
    Ghezzi C, Meinild AK, Murer H, Forster IC (2011) Voltage- and substrate-dependent interactions between sites in putative re-entrant domains of a Na(+)-coupled phosphate cotransporter. Pflugers Arch - Eur J Physiol 461:645–663.  https://doi.org/10.1007/s00424-011-0948-z CrossRefGoogle Scholar
  45. 45.
    Ghezzi C, Murer H, Forster IC (2009) Substrate interactions of the electroneutral Na+−coupled inorganic phosphate cotransporter (NaPi-IIc). J Physiol 587:4293–4307.  https://doi.org/10.1113/jphysiol.2009.175596 PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Gisler SM, Kittanakom S, Fuster D, Wong V, Bertic M, Radanovic T, Hall RA, Murer H, Biber J, Markovich D, Moe OW, Stagljar I (2008) Monitoring protein-protein interactions between the mammalian integral membrane transporters and PDZ-interacting partners using a modified split-ubiquitin membrane yeast two-hybrid system. Mol Cell Proteomics 7:1362–1377.  https://doi.org/10.1074/mcp.M800079-MCP200 PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Gonzales AL, Lee W, Spencer SR, Oropeza RA, Chapman JV, Ku JY, Eskandari S (2007) Turnover rate of the gamma-aminobutyric acid transporter GAT1. J Membr Biol 220:33–51.  https://doi.org/10.1007/s00232-007-9073-5 PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Graham C, Nalbant P, Scholermann B, Hentschel H, Kinne RK, Werner A (2003) Characterization of a type IIb sodium-phosphate cotransporter from zebrafish (Danio rerio) kidney. Am J Physiol Ren Physiol 284:F727–F736CrossRefGoogle Scholar
  49. 49.
    Grewer C (2014) Shedding light on conformational dynamics of na(+)-coupled transporters. Biophys J 106:1549–1550.  https://doi.org/10.1016/j.bpj.2014.02.029 PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Hall JA, Pajor AM (2005) Functional characterization of a Na(+)-coupled dicarboxylate carrier protein from Staphylococcus aureus. J Bacteriol 187:5189–5194.  https://doi.org/10.1128/JB.187.15.5189-5194.2005 PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Hartmann CM, Wagner CA, Busch AE, Markovich D, Biber J, Lang F, Murer H (1995) Transport characteristics of a murine renal Na/Pi-cotransporter. Pflugers Arch - Eur J Physiol 430:830–836CrossRefGoogle Scholar
  52. 52.
    Hilfiker H, Hattenhauer O, Traebert M, Forster I, Murer H, Biber J (1998) Characterization of a murine type II sodium-phosphate cotransporter expressed in mammalian small intestine. Proc Natl Acad Sci U S A 95:14564–14569PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Hoffmann N, Thees M, Kinne R (1976) Phosphate transport by isolated renal brush border vesicles. Pflugers Arch 362:147–156PubMedCrossRefGoogle Scholar
  54. 54.
    Kaback HR, Sahin-Toth M, Weinglass AB (2001) The kamikaze approach to membrane transport. Nat Rev Mol Cell Biol 2:610–620.  https://doi.org/10.1038/35085077 PubMedCrossRefGoogle Scholar
  55. 55.
    Karlin A, Akabas MH (1998) Substituted-cysteine accessibility method. Methods Enzymol 293:123–145PubMedCrossRefGoogle Scholar
  56. 56.
    Kohl B, Wagner CA, Huelseweh B, Busch AE, Werner A (1998) The Na+−phosphate cotransport system (NaPi-II) with a cleaved protein backbone: implications on function and membrane insertion. J Physiol 508(Pt 2):341–350PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Kohler K, Forster IC, Lambert G, Biber J, Murer H (2000) The functional unit of the renal type IIa Na+/Pi cotransporter is a monomer. J Biol Chem 275:26113–26120PubMedCrossRefGoogle Scholar
  58. 58.
    Kohler K, Forster IC, Stange G, Biber J, Murer H (2002) Identification of functionally important sites in the first intracellular loop of the NaPi-IIa cotransporter. Am J Phys 282:F687–F696Google Scholar
  59. 59.
    Kohler K, Forster IC, Stange G, Biber J, Murer H (2002) Transport function of the renal type IIa Na+/Pi cotransporter is codetermined by residues in two opposing linker regions. J Gen Physiol 120:693–703PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Kohler K, Forster IC, Stange G, Biber J, Murer H (2003) Essential cysteine residues of the type IIa Na+/Pi cotransporter. Pflugers Arch - Eur J Physiol 446:203–210CrossRefGoogle Scholar
  61. 61.
    Krishnamurthy H, Piscitelli CL, Gouaux E (2009) Unlocking the molecular secrets of sodium-coupled transporters. Nature 459:347–355.  https://doi.org/10.1038/nature08143 PubMedCrossRefGoogle Scholar
  62. 62.
    Krofchick D, Huntley SA, Silverman M (2004) Transition states of the high-affinity rabbit Na(+)/glucose cotransporter SGLT1 as determined from measurement and analysis of voltage-dependent charge movements. Am J Phys Cell Physiol 287:C46–C54.  https://doi.org/10.1152/ajpcell.00008.2004 CrossRefGoogle Scholar
  63. 63.
    Lambert G, Forster IC, Biber J, Murer H (2000) Cysteine residues and the structure of the rat renal proximal tubular type II sodium phosphate cotransporter (rat NaPi IIa). J Membr Biol 176:133–141PubMedCrossRefGoogle Scholar
  64. 64.
    Lambert G, Forster IC, Stange G, Biber J, Murer H (1999) Properties of the mutant Ser-460-Cys implicate this site in a functionally important region of the type IIa Na+/Pi cotransporter protein. J Gen Physiol 114:637–652PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Lambert G, Forster IC, Stange G, Kohler K, Biber J, Murer H (2001) Cysteine mutagenesis reveals novel structure-function features within the predicted third extracellular loop of the type IIa Na+/Pi cotransporter. J Gen Physiol 117:533–546PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Lambert G, Traebert M, Hernando N, Biber J, Murer H (1999) Studies on the topology of the renal type II NaPi-cotransporter. Pflugers Arch - Eur J Physiol 437:972–978CrossRefGoogle Scholar
  67. 67.
    Longpre JP, Sasseville LJ, Lapointe JY (2012) Simulated annealing reveals the kinetic activity of SGLT1, a member of the LeuT structural family. J Gen Physiol 140:361–374.  https://doi.org/10.1085/jgp.201210822 PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Loo DD, Hazama A, Supplisson S, Turk E, Wright EM (1993) Relaxation kinetics of the Na+/glucose cotransporter. Proc Natl Acad Sci U S A 90:5767–5771PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Loo DD, Hirayama BA, Gallardo EM, Lam JT, Turk E, Wright EM (1998) Conformational changes couple Na+ and glucose transport. Proc Natl Acad Sci U S A 95:7789–7794PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Loo DD, Hirayama BA, Karakossian MH, Meinild AK, Wright EM (2006) Conformational dynamics of hSGLT1 during Na+/glucose cotransport. J Gen Physiol 128:701–720.  https://doi.org/10.1085/jgp.200609643 PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Loo DD, Jiang X, Gorraitz E, Hirayama BA, Wright EM (2013) Functional identification and characterization of sodium binding sites in Na symporters. Proc Natl Acad Sci U S A 110:E4557–E4566.  https://doi.org/10.1073/pnas.1319218110 PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Lu CC, Hilgemann DW (1999) GAT1 (GABA:Na+:Cl-) cotransport function. Steady state studies in giant Xenopus oocyte membrane patches. J Gen Physiol 114:429–444PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Mackenzie B, Loo DD, Wright EM (1998) Relationships between Na+/glucose cotransporter (SGLT1) currents and fluxes. J Membr Biol 162:101–106PubMedCrossRefGoogle Scholar
  74. 74.
    Magagnin S, Werner A, Markovich D, Sorribas V, Stange G, Biber J, Murer H (1993) Expression cloning of human and rat renal cortex Na/Pi cotransport. Proc Natl Acad Sci U S A 90:5979–5983PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Mager S, Cao Y, Lester HA (1998) Measurement of transient currents from neurotransmitter transporters expressed in Xenopus oocytes. Methods Enzymol 296:551–566PubMedCrossRefGoogle Scholar
  76. 76.
    Mager S, Naeve J, Quick M, Labarca C, Davidson N, Lester HA (1993) Steady states, charge movements, and rates for a cloned GABA transporter expressed in Xenopus oocytes. Neuron 10:177–188PubMedCrossRefGoogle Scholar
  77. 77.
    Mancusso R, Gregorio GG, Liu Q, Wang DN (2012) Structure and mechanism of a bacterial sodium-dependent dicarboxylate transporter. Nature 491:622–626.  https://doi.org/10.1038/nature11542 PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Meinild AK, Forster IC (2012) Using lithium to probe sequential cation interactions with GAT1. Am J Phys Cell Physiol 302:C1661–C1675.  https://doi.org/10.1152/ajpcell.00446.2011 CrossRefGoogle Scholar
  79. 79.
    Mitchell P (1957) A general theory of membrane transport from studies of bacteria. Nature 180:134–136PubMedCrossRefGoogle Scholar
  80. 80.
    Mulligan C, Fenollar-Ferrer C, Fitzgerald GA, Vergara-Jaque A, Kaufmann D, Li Y, Forrest LR, Mindell JA (2016) The bacterial dicarboxylate transporter VcINDY uses a two-domain elevator-type mechanism. Nat Struct Mol Biol 23:256–263.  https://doi.org/10.1038/nsmb.3166 PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Mulligan C, Fitzgerald GA, Wang DN, Mindell JA (2014) Functional characterization of a Na+−dependent dicarboxylate transporter from Vibrio cholerae. J Gen Physiol 143:745–759.  https://doi.org/10.1085/jgp.201311141 PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Murer H, Ahearn G, Amstutz M, Biber J, Brown C, Gmaj P, Hagenbuch B, Malmstrom K, Mohrmann I, Mohrmann M et al (1985) Cotransport systems for inorganic sulfate and phosphate in small intestine and renal proximal tubule. Ann N Y Acad Sci 456:139–152PubMedCrossRefGoogle Scholar
  83. 83.
    Murer H, Hernando N, Forster I, Biber J (2000) Proximal tubular phosphate reabsorption: molecular mechanisms. Physiol Rev 80:1373–1409PubMedCrossRefGoogle Scholar
  84. 84.
    Murer H, Stern H, Burckhardt G, Storelli C, Kinne R (1980) Sodium-dependent transport of inorganic phosphate across the renal brush border membrane. Adv Exp Med Biol 128:11–23PubMedCrossRefGoogle Scholar
  85. 85.
    Nalbant P, Boehmer C, Dehmelt L, Wehner F, Werner A (1999) Functional characterization of a Na+-phosphate cotransporter (NaPi-II) from zebrafish and identification of related transcripts. J Physiol 520(Pt 1):79–89PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Pajor AM, Hirayama BA, Loo DD (1998) Sodium and lithium interactions with the Na+/Dicarboxylate cotransporter. J Biol Chem 273:18923–18929PubMedCrossRefGoogle Scholar
  87. 87.
    Parent L, Supplisson S, Loo DD, Wright EM (1992) Electrogenic properties of the cloned Na+/glucose cotransporter: II. A transport model under nonrapid equilibrium conditions. J Membr Biol 125:63–79PubMedGoogle Scholar
  88. 88.
    Patti M, Fenollar-Ferrer C, Werner A, Forrest LR, Forster IC (2016) Cation interactions and membrane potential induce conformational changes in NaPi-IIb. Biophys J 111:973–988.  https://doi.org/10.1016/j.bpj.2016.07.025 PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Patti M, Forster IC (2014) Correlating charge movements with local conformational changes of a na(+)-coupled cotransporter. Biophys J 106:1618–1629.  https://doi.org/10.1016/j.bpj.2014.02.028S0006-3495(14)00267-7 PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Patti M, Ghezzi C, Forster IC (2013) Conferring electrogenicity to the electroneutral phosphate cotransporter NaPi-IIc (SLC34A3) reveals an internal cation release step. Pflugers Arch - Eur J Physiol 465:1261–1279.  https://doi.org/10.1007/s00424-013-1261-9 CrossRefGoogle Scholar
  91. 91.
    Priest M, Bezanilla F (2015) Functional site-directed fluorometry. Adv Exp Med Biol 869:55–76.  https://doi.org/10.1007/978-1-4939-2845-3_4 PubMedCrossRefGoogle Scholar
  92. 92.
    Radanovic T, Gisler SM, Biber J, Murer H (2006) Topology of the type IIa Na+/P(i) cotransporter. J Membr Biol 212:41–49.  https://doi.org/10.1007/s00232-006-0033-2 PubMedCrossRefGoogle Scholar
  93. 93.
    Ravera S, Virkki LV, Murer H, Forster IC (2007) Deciphering PiT transport kinetics and substrate specificity using electrophysiology and flux measurements. Am J Phys Cell Physiol 293:C606–C620.  https://doi.org/10.1152/ajpcell.00064.2007 CrossRefGoogle Scholar
  94. 94.
    Sacktor B, Cheng L (1981) Sodium gradient-dependent phosphate transport in renal brush border membrane vesicles. Effect of an intravesicular greater than extravesicular proton gradient. J Biol Chem 256:8080–8084PubMedGoogle Scholar
  95. 95.
    Sahin-Toth M, Lawrence MC, Kaback HR (1994) Properties of permease dimer, a fusion protein containing two lactose permease molecules from Escherichia coli. Proc Natl Acad Sci U S A 91:5421–5425PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Samarzija I, Molnar V, Fromter E (1983) pH--dependence of phosphate absorption in rat renal proximal tubule. Proc Eur Dial Transplant Assoc 19:779–783PubMedGoogle Scholar
  97. 97.
    Schaffhauser DF, Patti M, Goda T, Miyahara Y, Forster IC, Dittrich PS (2012) An integrated field-effect microdevice for monitoring membrane transport in Xenopus laevis oocytes via lateral proton diffusion. PLoS One 7:e39238.  https://doi.org/10.1371/journal.pone.0039238PONE-D-12-05937 PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Segawa H, Kaneko I, Takahashi A, Kuwahata M, Ito M, Ohkido I, Tatsumi S, Miyamoto K (2002) Growth-related renal type II Na/Pi cotransporter. J Biol Chem 277:19665–19672PubMedCrossRefGoogle Scholar
  99. 99.
    Sonders MS, Amara SG (1996) Channels in transporters. Curr Opin Neurobiol 6:294–302PubMedCrossRefGoogle Scholar
  100. 100.
    Strevey J, Brunette MG, Beliveau R (1984) Effect of arginine modification on kidney brush-border-membrane transport activity. Biochem J 223:793–802PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Szczepanska-Konkel M, Yusufi AN, Lin JT, Dousa TP (1989) Structural requirement of monophosphates for inhibition of Na+-Pi cotransport in renal brush border membrane. Biochem Pharmacol 38:4191–4197PubMedCrossRefGoogle Scholar
  102. 102.
    Uwai Y, Arima R, Takatsu C, Furuta R, Kawasaki T, Nabekura T (2014) Sodium-phosphate cotransporter mediates reabsorption of lithium in rat kidney. Pharmacol Res 87:94–98.  https://doi.org/10.1016/j.phrs.2014.06.012 PubMedCrossRefGoogle Scholar
  103. 103.
    Vergara-Jaque A, Fenollar-Ferrer C, Kaufmann D, Forrest LR (2015) Repeat-swap homology modeling of secondary active transporters:updated protocol and prediction of elevator-type mechanisms. Front Pharmacol 6:1–12.  https://doi.org/10.3389/fphar.2015.00183 CrossRefGoogle Scholar
  104. 104.
    Vergara-Jaque A, Fenollar-Ferrer C, Mulligan C, Mindell JA, Forrest LR (2015) Family resemblances: a common fold for some dimeric ion-coupled secondary transporters. J Gen Physiol 146:423–434.  https://doi.org/10.1085/jgp.201511481 PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Virkki LV, Forster IC, Bacconi A, Biber J, Murer H (2005) Functionally important residues in the predicted 3rd transmembrane domain of the type IIa sodium-phosphate co-transporter (NaPi-IIa). J Membr Biol 206:227–238PubMedCrossRefGoogle Scholar
  106. 106.
    Virkki LV, Forster IC, Biber J, Murer H (2005) Substrate interactions in the human type IIa sodium-phosphate cotransporter (NaPi-IIa). Am J Phys 288:F969–F981Google Scholar
  107. 107.
    Virkki LV, Murer H, Forster IC (2006) Mapping conformational changes of the type IIb Na+/Pi cotransporter by voltage clamp fluorometry. J Biol Chem 281:28837–28849PubMedCrossRefGoogle Scholar
  108. 108.
    Virkki LV, Murer H, Forster IC (2006) Voltage clamp fluorometric measurements on a type II Na+-coupled Pi cotransporter: shedding light on substrate binding order. J Gen Physiol 127:539–555PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Weiss JN (1997) The hill equation revisited: uses and misuses. FASEB J 11:835–841PubMedCrossRefGoogle Scholar
  110. 110.
    Werner A, Patti M, Zinad HS, Fearn A, Laude A, Forster I (2016) Molecular determinants of transport function in zebrafish Slc34a Na-phosphate transporters. Am J Phys Regul Integr Comp Phys 311:R1213–R1222.  https://doi.org/10.1152/ajpregu.00020.2016 CrossRefGoogle Scholar
  111. 111.
    Xiao Y, Boyer CJ, Vincent E, Dugre A, Vachon V, Potier M, Beliveau R (1997) Involvement of disulphide bonds in the renal sodium/phosphate co-transporter NaPi-2. Biochem J 323(Pt 2):401–408PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Yamashita A, Singh SK, Kawate T, Jin Y, Gouaux E (2005) Crystal structure of a bacterial homologue of Na+/Cl-dependent neurotransmitter transporters. Nature 437:215–223.  https://doi.org/10.1038/nature03978 PubMedCrossRefGoogle Scholar
  113. 113.
    Yernool D, Boudker O, Jin Y, Gouaux E (2004) Structure of a glutamate transporter homologue from Pyrococcus horikoshii. Nature 431:811–818.  https://doi.org/10.1038/nature03018 PubMedCrossRefGoogle Scholar
  114. 114.
    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 148:65–78PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Ion Channels and Human Diseases LaboratoryFlorey Institute of Neuroscience and Mental HealthParkvilleAustralia

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