Reassessment of Models of Facilitated Transport and Cotransport

The Journal of Membrane Biology - Tập 234 - Trang 75-112 - 2010
Richard J. Naftalin1
1Department of Physiology, King's College London, London, UK

Tóm tắt

Most membrane transport models are determinate, requiring the transported ligand(s) to bind initially to a vacant site, which undergoes translation and releases ligand to the alternate side. The carrier reverts to its initial position to complete the net transport cycle. Ligand affinity may change during translation, but this must be compensated by an equivalent energy change(s) within the transport cycle. However, any asymmetric cyclic equilibrium deduced on this basis is thermodynamically fallacious. Determinate cotransport models imply lossless stoichiometric relationships between the complexed cotransported ligands. Independent ligand leakage apart from the mobile cotransport complex must occur outside the canonical cotransport pathway. In contrast, stochastic transport models assume independent ligand diffusion through a variably occluded channel(s) containing binding sites where ligands may undergo bimolecular exchanges. Energy dissipation is intrinsic to all stochastic transport models and occurs within the primary transport pathway. Frictional interactions within a shared path generate flow coupling between ligands. The primary driving forces causing transmembrane ligand flows are their electrochemical potential differences between the external solutions. Demonstrations that ligand exchanges in CLC and neurotransmitter transporters can be multimodal, encompassing both “channel”-like high and “transporter”-like lower conductance states and have independently regulated import and export exchange fluxes are major challenges to determinate models but are explicable by transient widening of a close-encounter region within the channel, leading to decreased coupling and enhanced efflux.

Tài liệu tham khảo

Abramson J, Smirnova I, Kasho V, Verner G, Kaback HR, Iwata S (2003) Structure and mechanism of the lactose permease of Escherichia coli. Science 301:610–615 Abramson J, Iwata S, Kaback HR (2004a) Lactose permease as a paradigm for membrane transport proteins [review]. Mol Membr Biol 21:227–236 Abramson J, Kaback HR, Iwata S (2004b) Structural comparison of lactose permease and the glycerol-3-phosphate antiporter: members of the major facilitator superfamily. Curr Opin Struct Biol 14:413–419 Accardi A, Miller C (2004) Secondary active transport mediated by a prokaryotic homologue of ClC Cl− channels. Nature 427:803–807 Accardi A, Kolmakova-Partensky L, Williams C, Miller C (2004) Ionic currents mediated by a prokaryotic homologue of CLC Cl− channels. J Gen Physiol 123:109–119 Accardi A, Walden M, Nguitragool W, Jayaram H, Williams C, Miller C (2005) Separate ion pathways in a Cl−/H+ exchanger. J Gen Physiol 126:563–570 Accardi A, Lobet S, Williams C, Miller C, Dutzler R (2006) Synergism between halide binding and proton transport in a CLC-type exchanger. J Mol Biol 362:691–699 Adams SV, DeFelice LJ (2002) Flux coupling in the human serotonin transporter. Biophys J 83:3268–3282 Adams SV, DeFelice LJ (2003) Ionic currents in the human serotonin transporter reveal inconsistencies in the alternating access hypothesis. Biophys J 85:1548–1559 Alekov AK, Fahlke C (2009) Channel-like slippage modes in the human anion/proton exchanger ClC-4. J Gen Physiol 133:485–496 Baker GF, Naftalin RJ (1979) Evidence of multiple operational affinities for d-glucose inside the human erythrocyte membrane. Biochim Biophys Acta 550:474–484 Baker GF, Widdas WF (1973) Asymmetry of facilitated transfer system for hexoses in human red-cells and simple kinetics of a 2 component model. J Physiol 231:143–165 Bergsdorf EY, Zdebik AA, Jentsch TJ (2009) Residues important for nitrate/proton coupling in plant and mammalian CLC transporters. J Biol Chem 284:11184–11193 Binda F, Dipace C, Bowton E, Robertson SD, Lute BJ, Fog JU, Zhang M, Sen N, Colbran RJ, Gnegy ME, Gether U, Javitch JA, Erreger K, Galli A (2008) Syntaxin 1A interaction with the dopamine transporter promotes amphetamine-induced dopamine efflux. Mol Pharmacol 74:1101–1108 Brahm J (1977) Temperature-dependent changes of chloride transport kinetics in human red cells. J Gen Physiol 70:283–306 Brahm J (1983) Kinetics of glucose transport in human erythrocytes. J Physiol 339:339–354 Brahm J, Wieth JO (1977) Separative pathways for urea and water, and for chloride in chicken erythrocytes. J Physiol 266:727–749 Carruthers A, Dezutter J, Ganguly A, Devaskar S (2009) Will the original glucose transporter isoform please stand up! Am J Physiol Endocrinol Metab 297:E836–E848 Centelles JJ, Kinne RK, Heinz E (1991) Energetic coupling of Na–glucose cotransport. Biochim Biophys Acta 1065:239–249 Chen JG, Rudnick G (2000) Permeation and gating residues in serotonin transporter 1. Proc Natl Acad Sci USA 97:1044–1049 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 Chen XZ, Coady MJ, Jalal F, Wallendorff B, Lapointe JY (1997) Sodium leak pathway and substrate binding order in the Na+–glucose cotransporter. Biophys J 73:2503–2510 Ciccone MA, Timmons M, Phillips A, Quick MW (2008) Calcium/calmodulin-dependent kinase II regulates the interaction between the serotonin transporter and syntaxin 1A. Neuropharmacology 55:763–770 Cloherty EK, Heard KS, Carruthers A (1996) Human erythrocyte sugar transport is incompatible with available carrier models. Biochemistry 35:10411–10421 Dauterive R, Laroux S, Bunn R, Chaisson A, Sanson T, Reed B (1996) C-terminal mutations that alter the turnover number for 3-O-methylglucose transport by GLUT1 and GLUT4. J Biol Chem 271:11414–11421 De Angelo A, Monachello D, Ephritikhine G, Frachisse JM, Thomine S, Gambale F, Barbier-Brygoo H (2006) The nitrate/proton antiporter AtCLCa mediates nitrate accumulation in plant vacuoles. Nature 442:939–942 Deves R, Krupka RM (1981) Evidence for a two-state mobile carrier mechanism in erythrocyte choline transport: effects of substrate analogs on inactivation of the carrier by N-ethylmaleimide. J Membr Biol 61:21–30 Diallinas G (2008) Biochemistry. An almost-complete movie. Science 322:1644–1645 DiPolo R, Beauge L (2006) Sodium/calcium exchanger: influence of metabolic regulation on ion carrier interactions. Physiol Rev 86:155–203 Dutzler R (2007) A structural perspective on ClC channel and transporter function. FEBS Lett 581:2839–2844 Dutzler R, Campbell EB, MacKinnon R (2003) Gating the selectivity filter in ClC chloride channels. Science 300:108–112 Eddy A (1982) Mechanisms of solute transport in selected eukaryotic micro-organisms. Adv Microb Physiol 23(1–78):269–270 Edwards PA (1973) Evidence for the carrier model of transport from the inhibition by N-ethylmaleimide of choline transport across the human red cell membrane 2. Biochim Biophys Acta 311:123–140 Ege R (1927) The dispersed phase of the blood corpuscles 1. Biochem J 21:967–970 Ellory JC, Guizouarn H, Borgese F, Bruce LJ, Wilkins RJ, Stewart GW (2009) Review. Leaky Cl—HCO3-exchangers: cation fluxes via modified AE1. Philos Trans R Soc Lond B Biol Sc. 364:189–194 Eraly SA (2008) Implications of the alternating access model for organic anion transporter kinetics. J Membr Biol 226:35–42 Erreger K, Grewer C, Javitch JA, Galli A (2008) Currents in response to rapid concentration jumps of amphetamine uncover novel aspects of human dopamine transporter function. J Neurosci 28:976–989 Eskandari S, Wright EM, Loo DD (2005) Kinetics of the reverse mode of the Na+/glucose cotransporter. J Membr Biol 204:23–32 Essig A, Caplan SR (1989) Water movement: does thermodynamic interpretation distort reality? Am J Physiol 256:C694–C698 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 321:810–814 Finkelstein A (1987) Water movement through lipid bilayers, pores, and plasma membranes: theory and reality. Wiley, New York Fischer JF, Cho AK (1979) Chemical release of dopamine from striatal homogenates: evidence for an exchange diffusion model 1. J Pharmacol Exp Ther 208:203–209 Fog JU, Khoshbouei H, Holy M, Owens WA, Vaegter CB, Sen N, Nikandrova Y, Bowton E, McMahon DG, Colbran RJ, Daws LC, Sitte HH, Javitch JA, Galli A, Gether U (2006) Calmodulin kinase II interacts with the dopamine transporter C terminus to regulate amphetamine-induced reverse transport. Neuron 51:417–429 Furman CA, Chen R, Guptaroy B, Zhang M, Holz RW, Gnegy M (2009) Dopamine and amphetamine rapidly increase dopamine transporter trafficking to the surface: live-cell imaging using total internal reflection fluorescence microscopy. J Neurosci 29:3328–3336 Geck P (1971) Properties of a carrier model for transport of sugars by human erythrocytes. Biochim Biophys Acta 241:462–472 Ginsburg H, Stein WD (1975) Zero-trans and infinite-cis uptake of galactose in human erythrocytes. Biochim Biophys Acta 382:353–368 Ginzburg BZ, Katchalsky A (1963) The frictional coefficients of the flows of non-electrolytes through artificial membranes. J Gen Physiol 47:403–418 Guan L, Kaback HR (2006) Lessons from lactose permease. Annu Rev Biophys Biomol Struct 35:67–91 Guptaroy B, Zhang M, Bowton E, Binda F, Shi L, Weinstein H, Galli A, Javitch JA, Neubig RR, Gnegy ME (2009) A juxtamembrane mutation in the N terminus of the dopamine transporter induces preference for an inward-facing conformation. Mol Pharmacol 75:514–524 Hankin BL, Stein WD, Lieb WR (1972) Rejection criteria for asymmetric carrier and their application to glucose transport in human red blood-cell. Biochim Biophys Acta 288:114–126 Hilber B, Scholze P, Dorostkar MM, Sandtner W, Holy M, Boehm S, Singer EA, Sitte HH (2005) Serotonin-transporter mediated efflux: a pharmacological analysis of amphetamines and non-amphetamines. Neuropharmacology 49:811–819 Hilgemann DW, Lu CC (1999) GAT1 (GABA:Na+:Cl–) cotransport function. Database reconstruction with an alternating access model. J Gen Physiol 114:459–475 Hille B (2001) Ion channels of excitable membranes. Sinauer, Sunderland, MA Holman GD, Naftalin RJ (1975) Galactose transport across the serosal border of rabbit ileum and its role in intracellular accumulation 9. Biochim Biophys Acta 382:230–245 Holman GD, Naftalin RJ (1976) Transport of 3-O-methyl d-glucose and beta-methyl d-glucoside by rabbit ileum. Biochim Biophys Acta 433:597–614 Jardetzky O (1966) Simple allosteric model for membrane pumps. Nature 211:969–970 Jarvis SM, Hammond JR, Paterson AR, Clanachan AS (1983) Nucleoside transport in human erythrocytes. A simple carrier with directional symmetry in fresh cells, but with directional asymmetry in cells from outdated blood. Biochem J 210:457–461 Johnson LA, Furman CA, Zhang M, Guptaroy B, Gnegy ME (2005) Rapid delivery of the dopamine transporter to the plasmalemmal membrane upon amphetamine stimulation. Neuropharmacology 49:750–758 Joost HG, Bell GI, Best JD, Birnbaum MJ, Charron MJ, Chen YT, Doege H, James DE, Lodish HF, Moley KH, Moley JF, Mueckler M, Rogers S, Schürmann A, Seino S, Thorens B (2002) Nomenclature of the GLUT/SLC2A family of sugar/polyol transport facilitators. Am J Physiol Endocrinol Metab 282:E974–E976 Kahlig KM, Binda F, Khoshbouei H, Blakely RD, McMahon DG, Javitch JA, Galli A (2005) Amphetamine induces dopamine efflux through a dopamine transporter channel. Proc Natl Acad Sci USA 102:3495–3500 Kanner BI (1978) Active transport of gamma-aminobutyric acid by membrane vesicles isolated from rat brain. Biochemistry 17:1207–1211 Kantor L, Gnegy ME (1998) Protein kinase C inhibitors block amphetamine-mediated dopamine release in rat striatal slices. J Pharmacol Exp Ther 284:592–598 Kedem O, Caplan SR (1965) Degree of coupling and its relation to efficiency of energy conversion. Trans Faraday Soc 61:1897–1911 Kedem O, Katchalsky A (1963a) Permeability of composite membranes. 1. Electric current, volume flow and flow of solute through membranes. Trans Faraday Soc 59:1918–1930 Kedem O, Katchalsky A (1963b) Permeability of composite membranes. 2. Parallel elements. Trans Faraday Soc 59:1931–1940 Kedem O, Katchalsky A (1963c) Permeability of composite membranes. 3. Series array of elements. Trans Faraday Soc 59:1941–1953 Kessler M, Semenza G (1983) The small-intestinal Na+, d-glucose cotransporter: an asymmetric gated channel (or pore) responsive to delta psi. J Membr Biol 76:27–56 Khoshbouei H, Wang H, Lechleiter JD, Javitch JA, Galli A (2003) Amphetamine-induced dopamine efflux. A voltage-sensitive and intracellular Na+-dependent mechanism. J Biol Chem 278:12070–12077 Klein MJ (1955) Principle of detailed balance. Phys Rev 97:1446–1447 Kondepudi DK, Prigogine I (1998) Modern thermodynamics: from heat engines to dissipative structures. Wiley, Chichester, UK Krupka RM (1990) Expression of substrate specificity in facilitated transport systems. J Membr Biol 117:69–78 Kuang Z, Mahankali U, Beck TL (2007) Proton pathways and H+/Cl–stoichiometry in bacterial chloride transporters. Proteins 68:26–33 Lapointe J, Sasseville L, Longpré J (2009) Alternating carrier models and the energy conservation laws. Biophys J 97:2648–2650 LeFevre PG, LeFevre ME (1952) The mechanism of glucose transfer into and out of the human red cell. J Gen Physiol 35:891–906 Leitch JM, Carruthers A (2009) Alpha- and beta-monosaccharide transport in human erythrocytes. Am J Physiol 296:C151–C161 Levin E, Quick M, Zhou M (2009) Crystal structure of a bacterial homologue of the kidney urea transporter. Nature 462:757–761 Levy L, Warr O, Attwell D (1998) Stoichiometry of the glial glutamate transporter GLT-1 expressed inducibly in a Chinese hamster ovary cell line selected for low endogenous Na+-dependent glutamate uptake. J Neurosci 18:9620–9628 Lewis GN (1925) A new principle of equilibrium. Proc Natl Acad Sci USA 11:179–183 Li Y, Petroski J, El-Sayed M (2000) Activation energy of the reaction between hexacyanoferrate(III) and thiosulfate ions catalyzed by platinum nanoparticles. J Phys Chem B Condens Matter Mater Surf Interfaces Biophys 104:10956–10959 Lieb WR, Stein WD (1974) Testing and characterizing the simple carrier. Biochim Biophys Acta 373:178–196 Lim HH, Miller C (2009) Intracellular proton-transfer mutants in a CLC Cl–/H+ exchanger. J Gen Physiol 133:131–138 Lowe AG, Walmsley AR (1986) The kinetics of glucose transport in human red blood cells. Biochim Biophys Acta 857:146–154 MacIver B, Smith C, Hill W, Zeidel M (2008) Functional characterization of mouse urea transporters UT-A2 and UT-A3 expressed in purified Xenopus laevis oocyte plasma membranes. Am J Physiol 294:F956–F964 Mackenzie B, Loo DD, Panayotova-Heiermann M, Wright EM (1996) Biophysical characteristics of the pig kidney Na+/glucose cotransporter SGLT2 reveal a common mechanism for SGLT1 and SGLT2. J Biol Chem 271:32678–32683 Mackenzie B, Loo DD, Wright EM (1998) Relationships between Na+/glucose cotransporter (SGLT1) currents and fluxes. J Membr Biol 162:101–106 Majumdar DS, Smirnova I, Kasho V, Nir E, Kong X, Weiss S, Kaback HR (2007) Single-molecule FRET reveals sugar-induced conformational dynamics in Lac. Proc Natl Acad Sci USA 104:12640–12645 Mazei-Robison MS, Bowton E, Holy M, Schmudermaier M, Freissmuth M, Sitte HH, Galli A, Blakely RD (2008) Anomalous dopamine release associated with a human dopamine transporter coding variant. J Neurosci 28:7040–7046 Mikulecky DC (2001) Network thermodynamics and complexity: a transition to relational systems theory. Comput Chem 25:369–391 Miller DM (1971) The kinetics of selective biological transport. V. Further data on the erythrocyte–monosaccharide transport system. Biophys J 11:915–923 Miller C, Nguitragool W (2009) A provisional transport mechanism for a chloride channel-type Cl–/H+ exchanger. Philos Trans R Soc B-Biol Sci 364:175–180 Morth J, Poulsen H, Toustrup-Jensen M, Schack V, Egebjerg J, Andersen J, Vilsen B, Nissen P (2009) The structure of the Na+, K+-ATPase and mapping of isoform differences and disease-related mutations. Philos Trans R Soc B-Biol Sci 364:217–227 Naftalin RJ (2008a) Alternating carrier models of asymmetric glucose transport violate the energy conservation laws. Biophys J 95:4300–4314 Naftalin RJ (2008b) Osmotic water transport with glucose in GLUT2 and SGLT. Biophys J 94:3912–3923 Naftalin R, Arain M (1999) Interactions of sodium pentobarbital with d-glucose and l-sorbose transport in human red cells. Biochim Biophys Acta 1419:78–88 Naftalin RJ, Holman GD (1974) The role of Na as a determinant of the asymmetric permeability of rabbit ileal brush-border to d-galactose. Biochim Biophys Acta 373:453–470 Naftalin RJ, Smith PM, Roselaar SE (1985) Evidence for non-uniform distribution of d-glucose within human red cells during net exit and counterflow. Biochim Biophys Acta 820:235–249 Naftalin RJ, Green N, Cunningham P (2007) Lactose permease H+-lactose symporter: mechanical switch or Brownian ratchet? Biophys J 92:3474–3491 Nelson PJ, Rudnick G (1979) Coupling between platelet 5-hydroxytryptamine and potassium transport. J Biol Chem 254:10084–10089 Nguitragool W, Miller C (2007) Inaugural article. CLC Cl/H+ transporters constrained by covalent cross-linking. Proc Natl Acad Sci USA 104:20659–20665 Olkhova E, Hunte C, Screpanti E, Padan E, Michel H (2006) Multiconformation continuum electrostatics analysis of the NhaA Na+/H+ antiporter of Escherichia coli with functional implications 1. Proc Natl Acad Sci USA 103:2629–2634 Onsager L (1931a) Reciprocal relations in irreversible processes. I. Phys Rev 37:405–426 Onsager L (1931b) Reciprocal relations in irreversible processes. II. Phys Rev 38:2265–2279 Panayotova-Heiermann M, Loo DD, Wright EM (1995) Kinetics of steady-state currents and charge movements associated with the rat Na+/glucose cotransporter. J Biol Chem 270:27099–27105 Patlak CS, Goldstein DA, Hoffman JF (1963) The flow of solute and solvent across a two-membrane system. J Theor Biol 5:426–442 Peusner L (1986) Hierarchies of energy-conversion processes. 3. Why are Onsager equations reciprocal––the Euclidean geometry of fluctuation––dissipation space. J Theor Biol 122:125–155 Pifl C, Singer E (1999) Ion dependence of carrier-mediated release in dopamine or norepinephrine transporter–transfected cells questions the hypothesis of facilitated exchange diffusion. Mol Pharmacol 56:1047–1054 Prausnitz JM, Lichtenthaler RN, Azevedo EGD (1986) Molecular thermodynamics of fluid-phase equilibria. Prentice-Hall, Englewood Cliffs, NJ Prigogine I (1968) Introduction to thermodynamics of irreversible processes. Interscience, New York Regen DM, Morgan HE (1964) Studies of glucose-transport system in rabbit erythrocyte. Biochim Biophys Acta 79:151–166 Regen DM, Tarpley HL (1974) Anomalous transport kinetics and glucose carrier hypothesis. Biochim Biophys Acta 339:218–233 Reith ME, Xu C, Chen NH (1997) Pharmacology and regulation of the neuronal dopamine transporter. Eur J Pharmacol 324:1–10 Robertson S, Matthies H, Galli A (2009) A closer look at amphetamine-induced reverse transport and trafficking of the dopamine and norepinephrine transporters. Mol Neurobiol 39:73–80 Rudnick G (2006) Serotonin transporters-structure and function. J Membr Biol 213:101–110 Rudnick G, Nelson PJ (1978) Reconstitution of 5-hydroxytryptamine transport from cholate-disrupted platelet plasma membrane vesicles. Biochemistry 17:5300–5303 Saint-Martin P, Lespinat PA, Fauque G, Berlier Y, Legall J, Moura I, Teixeira M, Xavier AV, Moura JJ (1988) Hydrogen production and deuterium–proton exchange reactions catalyzed by desulfovibrio nickel(II)-substituted rubredoxins. Proc Natl Acad Sci USA 85:9378–9380 Saunders C, Ferrer JV, Shi L, Chen J, Merrill G, Lamb ME, Leeb-Lundberg LM, Carvelli L, Javitch JA, Galli A (2000) Amphetamine-induced loss of human dopamine transporter activity: an internalization-dependent and cocaine-sensitive mechanism. Proc Natl Acad Sci USA 97:6850–6855 Schwartz JW, Blakely RD, DeFelice LJ (2003) Binding and transport in norepinephrine transporters. Real-time, spatially resolved analysis in single cells using a fluorescent substrate. J Biol Chem 278:9768–9777 Schwartz JW, Novarino G, Piston DW, DeFelice LJ (2005) Substrate binding stoichiometry and kinetics of the norepinephrine transporter. J Biol Chem 280:19177–19184 Semenza G, Kessler M, Hosang M, Weber J, Schmidt U (1984) Biochemistry of the Na+, d-glucose cotransporter of the small-intestinal brush-border membrane. The state of the art in 1984. Biochim Biophys Acta 779:343–379 Semenza G, Kessler M, Schmidt U, Venter JC, Fraser CM (1985) The small-intestinal sodium-glucose cotransporter(s) 1. Ann NY Acad Sci 456:83–96 Singh SK, Yamashita A, Gouaux E (2007) Antidepressant binding site in a bacterial homologue of neurotransmitter transporters. Nature 448:952–956 Singh SK, Piscitelli CL, Yamashita A, Gouaux E (2008) A competitive inhibitor traps LeuT in an open-to-out conformation 1. Science 322:1655–1661 Sitte HH, Hiptmair B, Zwach J, Pifl C, Singer EA, Scholze P (2001) Quantitative analysis of inward and outward transport rates in cells stably expressing the cloned human serotonin transporter: inconsistencies with the hypothesis of facilitated exchange diffusion. Mol Pharmacol 59:1129–1137 Smirnova I, Kasho V, Choe JY, Altenbach C, Hubbell WL, Kaback HR (2007) Sugar binding induces an outward facing conformation of LacY 1. Proc Natl Acad Sci USA 104:16504–16509 Stein WD (1989) Kinetics of transport: analyzing, testing, and characterizing models using kinetic approaches. Methods Enzymol 171:23–62 Sulzer D, Sonders MS, Poulsen NW, Galli A (2005) Mechanisms of neurotransmitter release by amphetamines: a review. Prog Neurobiol 75:406–433 Supplisson S, Roux MJ (2002) Why glycine transporters have different stoichiometries. FEBS Lett 529:93–101 Tolman RC (1925) The principle of microscopic reversibility. Proc Natl Acad Sci USA 11:436–439 Turner RJ (1981) Kinetic analysis of a family of cotransport models. Biochim Biophys Acta 649:269–280 Ussing HH (1949) The active ion transport through the isolated frog skin in the light of tracer studies. Acta Physiol Scand 17:1–37 Van Camp B, Crow R, Peng Y, Varela M (2007) Amino acids that confer transport of raffinose and maltose sugars in the raffinose permease (RafB) of Escherichia coli as implicated by spontaneous mutations at Val-35, Ser-138, Ser-139, Gly-389 and Ile-391. J Membr Biol 220:87–95 Walden M, Accardi A, Wu F, Xu C, Williams C, Miller C (2007) Uncoupling and turnover in a Cl–/H+ exchange transporter. J Gen Physiol 129:317–329 Wegscheider R (1901) Simultaneous equations and the relationships between thermodynamic and reaction kinetic homogeneous system. Z Phys Chem Stoch Verwand E 39:257–303 Weyand S, Shimamura T, Yajima S, Suzuki S, Mirza O, Krusong K, Carpenter EP, Rutherford NG, Hadden JM, O’Reilly J, Ma P, Saidijam M, Patching SG, Hope RJ, Norbertczak HT, Roach PC, Iwata S, Henderson PJ, Cameron AD (2008) Structure and molecular mechanism of a nucleobase-cation-symport-1 family transporter. Science 322:709–713 Whitesell RR, Regen DM, Beth AH, Pelletier DK, Abumrad NA (1989) Activation energy of the slowest step in the glucose carrier cycle: break at 23 degrees C and correlation with membrane lipid fluidity. Biochemistry 28:5618–5625 Wilbrandt W, Rosenberg T (1961) The concept of carrier transport and its corollaries in pharmacology. Pharmacol Rev 13:109–183 Zerangue N, Kavanaugh MP (1996) Flux coupling in a neuronal glutamate transporter. Nature 383:634–637 Zeuthen T, Zeuthen E (2007) The mechanism of water transport in Na+-coupled glucose transporters expressed in Xenopus oocytes. Biophys J 93:1413–1416 Zeuthen T, Zeuthen E, Macaulay N (2007) Water transport by GLUT2 expressed in Xenopus laevis oocytes. J Physiol 579:345–361 Zifarelli G, Pusch M (2009) Conversion of the 2 Cl–/1 H+ antiporter ClC-5 in a NO3–/H+ antiporter by a single point mutation. EMBO J 28:175–182 Zomot E, Bendahan A, Quick M, Zhao Y, Javitch JA, Kanner BI (2007) Mechanism of chloride interaction with neurotransmitter:sodium symporters. Nature 449:726–730