Chapter 6
6.1 Introduction
Review
Hille, B., 2001. Ion channels of excitable membranes. Sinauer Associates, Inc.
Sunderland, MA.
Hille, B., Armstrong, C. M., and MacKinnon, R., 1999. Ion channels: from idea to
reality. Nat. Med. v. 5 p. 1105–1109.
6.2 Channels and carriers are the main types of membrane transport proteins
Research
Jentsch, T. J., Hübner, C. A., and Fuhrmann, J. C., 2004. Ion channels: Function
unravelled by dysfunction. Nat. Cell Biol. v. 6 p. 1039–1047.
+
6.5 K channels catalyze selective and rapid ion permeation
Review
Berneche, S., and Roux, B., 2001. Energetics of ion conduction through the K+ channel.
Nature v. 414 p. 73–77.
Choe, S., 2002. Potassium channel structures. Nat. Rev. Neurosci. v. 3 p. 115–121.
Hille, B., Armstrong, C. M., and MacKinnon, R., 1999. Ion channels: from idea to
reality. Nat. Med. v. 5 p. 1105–1109.
Miller, C., 2000. An overview of the potassium channel family. Genome Biol. v. 1 p.
R0004.
Morais-Cabral, J. H., Zhou, Y., and MacKinnon, R., 2001. Energetic optimization of ion
conduction rate by the K+ selectivity filter. Nature v. 414 p. 37–42.
Research
Doyle, D. A., Morais Cabral, J., Pfuetzner, R. A., Kuo, A., Gulbis, J. M., Cohen, S. L.,
Chait, B. T., and MacKinnon, R., 1998. The structure of the potassium channel:
molecular basis of K+ conduction and selectivity. Science v. 280 p. 69–77.
Gutman, G. A., et al., 2003. International Union of Pharmacology. XLI. Compendium of
voltage-gated ion channels: potassium channels. Pharmacol. Rev. v. 55 p. 583–
586.
Zhou, Y., Morais-Cabral, J. H., Kaufman, A., and MacKinnon, R., 2001. Chemistry of
ion coordination and hydration revealed by a K+ channel-Fab complex at 2.0 Å
resolution. Nature v. 414 p. 43–48.
6.6 Different K+ channels use a similar gate coupled to different activating or inactivating
mechanisms
Review
Choe, S., 2002. Potassium channel structures. Nat. Rev. Neurosci. v. 3 p. 115–121.
Jiang, Y., Lee, A., Chen, J., Cadene, M., Chait, B. T., and MacKinnon, R., 2002. The
open pore conformation of potassium channels. Nature v. 417 p. 523–526.
Jiang, Y., Ruta, V., Chen, J., Lee, A., and MacKinnon, R., 2003. The principle of gating
charge movement in a voltage-dependent K+ channel. Nature v. 423 p. 42–48.
Kullmann, D. M., Rea, R., Spauschus, A., and Jouvenceau, A., 2001. The inherited
episodic ataxias: how well do we understand the disease mechanisms?
Neuroscientist v. 7 p. 80–88.
Tristani-Firouzi, M., and Sanguinetti, M. C., 2003. Structural determinants and
biophysical properties of HERG and KCNQ1 channel gating. J. Mol. Cell.
Cardiol. v. 35 p. 27–35.
Research
Jiang, Y., Lee, A., Chen, J., Cadene, M., Chait, B. T., and MacKinnon, R., 2002. Crystal
structure and mechanism of a calcium-gated potassium channel. Nature v. 417 p.
515–522.
Long, S. B., Campbell, E. B., and MacKinnon, R., 2005. Voltage sensor of Kv1.2:
structural basis of electromechanical coupling. Science v. 309 p. 903–908.
Long, S. B., Campbell, E. B., and MacKinnon, R., 2005. Crystal structure of a
mammalian voltage-dependent Shaker family K+ channel. Science v. 309 p. 897–
903.
Zhou, Y., Morais-Cabral, J. H., Kaufman, A., and MacKinnon, R., 2001. Chemistry of
ion coordination and hydration revealed by a K+ channel-Fab complex at 2.0 Å
resolution. Nature v. 414 p. 43–48.
6.7 Voltage-dependent Na+ channels are activated by membrane depolarization and
translate electrical signals
Review
Hondeghem, L. M., and Katzung, B. G., 1977. Time- and voltage-dependent interactions
of antiarrhythmic drugs with cardiac sodium channels. Biochim. Biophys. Acta v.
472 p. 373–398.
Vilin, Y. Y., and Ruben, P. C., 2001. Slow inactivation in voltage-gated sodium channels:
molecular substrates and contributions to channelopathies. Cell Biochem.
Biophys. v. 35 p. 171–190.
Yu, F. H., and Catterall, W. A., 2003. Overview of the voltage-gated sodium channel
family. Genome Biol. v. 4 p. 207–207.
Research
Chiamvimonvat, N., Pérez-García, M. T., Ranjan, R., Marban, E., and Tomaselli, G. F.,
1996. Depth asymmetries of the pore-lining segments of the Na+ channel revealed
by cysteine mutagenesis. Neuron v. 16 p. 1037–1047.
Isom, L. L., Ragsdale, D. S., De Jongh, K. S., Westenbroek, R. E., Reber, B. F., Scheuer,
T., and Catterall, W. A., 1995. Structure and function of the beta 2 subunit of
brain sodium channels, a transmembrane glycoprotein with a CAM motif. Cell v.
83 p. 433–442.
Kellenberger, S., Scheuer, T., and Catterall, W. A., 1996. Movement of the Na+ channel
inactivation gate during inactivation. J. Biol. Chem. v. 271 p. 30971–30979.
Mitrovic, N., George, A. L., and Horn, R., 2000. Role of domain 4 in sodium channel
slow inactivation. J. Gen. Physiol. v. 115 p. 707–718.
Ragsdale, D. S., McPhee, J. C., Scheuer, T., and Catterall, W. A., 1996. Common
molecular determinants of local anesthetic, antiarrhythmic, and anticonvulsant
block of voltage-gated Na+ channels. Proc. Natl. Acad. Sci. USA v. 93 p. 9270–
9275.
Rohl, C. A., Boeckman, F. A., Baker, C., Scheuer, T., Catterall, W. A., and Klevit, R. E.,
1999. Solution structure of the sodium channel inactivation gate. Biochemistry v.
38 p. 855–861.
Stühmer, W., Conti, F., Suzuki, H., Wang, X. D., Noda, M., Yahagi, N., Kubo, H., and
Numa, S., 1989. Structural parts involved in activation and inactivation of the
sodium channel. Nature v. 339 p. 597–603.
6.8 Epithelial Na+ channels regulate Na+ homeostasis
Review
Kellenberger, S., and Schild, L., 2002. Epithelial sodium channel/degenerin family of ion
channels: a variety of functions for a shared structure. Physiol. Rev. v. 82 p. 735–
767.
Research
Bruns, J. B., Hu, B., Ahn, Y. J., Sheng, S., Hughey, R. P., and Kleyman, T. R., 2003.
Multiple epithelial Na+ channel domains participate in subunit assembly. Am. J.
Physiol. Renal Physiol. v. 285 p. F600–F609.
Canessa, C. M., Schild, L., Buell, G., Thorens, B., Gautschi, I., Horisberger, J. D., and
Rossier, B. C., 1994. Amiloride-sensitive epithelial Na+ channel is made of three
homologous subunits. Nature v. 367 p. 463–467.
Chang, S. S., et al., 1996. Mutations in subunits of the epithelial sodium channel cause
salt wasting with hyperkalaemic acidosis, pseudohypoaldosteronism type 1. Nat.
Genet. v. 12 p. 248–253.
Hansson, J. H., Nelson-Williams, C., Suzuki, H., Schild, L., Shimkets, R., Lu, Y.,
Canessa, C., Iwasaki, T., Rossier, B., and Lifton, R. P., 1995. Hypertension
caused by a truncated epithelial sodium channel gamma subunit: genetic
heterogeneity of Liddle syndrome. Nat. Genet. v. 11 p. 76–82.
Palmer, L. G., and Andersen, O. S., 1989. Interactions of amiloride and small monovalent
cations with the epithelial sodium channel. Inferences about the nature of the
channel pore. Biophys. J. v. 55 p. 779–787.
Reif, M. C., Troutman, S. L., and Schafer, J. A., 1986. Sodium transport by rat cortical
collecting tubule. Effects of vasopressin and desoxycorticosterone. J. Clin. Invest.
v. 77 p. 1291–1298.
6.9 Plasma membrane Ca2+ channels activate intracellular functions
Review
Carafoli, E., 2003. The calcium-signalling saga: tap water and protein crystals. Nat. Rev.
Mol. Cell Biol. v. 4 p. 326–332.
Sather, W. A., and McCleskey, E. W., 2003. Permeation and selectivity in calcium
channels. Annu. Rev. Physiol. v. 65 p. 133–159.
Research
Ellinor, P. T., Yang, J., Sather, W. A., Zhang, J. F., and Tsien, R. W., 1995. Ca2+ channel
selectivity at a single locus for high-affinity Ca2+ interactions. Neuron v. 15 p.
1121–1132.
Erickson, M. G., Liang, H., Mori, M. X., and Yue, D. T., 2003. FRET two-hybrid
mapping reveals function and location of L-type Ca2+ channel CaM
preassociation. Neuron v. 39 p. 97–107.
Hess, P., and Tsien, R. W., 1984. Mechanism of ion permeation through calcium
channels. Nature v. 309 p. 453–456.
Liang, H., DeMaria, C. D., Erickson, M. G., Mori, M. X., Alseikhan, B. A., and Yue, D.
T., 2003. Unified mechanisms of Ca2+ regulation across the Ca2+ channel family.
Neuron v. 39 p. 951–960.
Lipkind, G. M., and Fozzard, H. A., 2003. Molecular modeling of interactions of
dihydropyridines and phenylalkylamines with the inner pore of the L-type Ca2+
channel. Mol. Pharmacol. v. 63 p. 499–511.
Serysheva, I. I., Ludtke, S. J., Baker, M. R., Chiu, W., and Hamilton, S. L., 2002.
Structure of the voltage-gated L-type Ca2+ channel by electron cryomicroscopy.
Proc. Natl. Acad. Sci. USA v. 99 p. 10370–10375.
Wu, X. S., Edwards, H. D., and Sather, W. A., 2000. Side chain orientation in the
selectivity filter of a voltage-gated Ca2+ channel. J. Biol. Chem. v. 275 p. 31778–
31785.
Yang, J., Ellinor, P. T., Sather, W. A., Zhang, J. F., and Tsien, R. W., 1993. Molecular
determinants of Ca2+ selectivity and ion permeation in L-type Ca2+ channels.
Nature v. 366 p. 158–161.
–
6.10 Cl channels serve diverse biological functions
Review
Bretag, A. H., 1987. Muscle chloride channels. Physiol. Rev. v. 67 p. 618–724.
Ellison, D. H., 2000. Divalent cation transport by the distal nephron: insights from
Bartter’s and Gitelman’s syndromes. Am. J. Physiol. Renal Physiol. v. 279 p.
F616–F625.
Jentsch, T. J., Stein, V., Weinreich, F., and Zdebik, A. A., 2002. Molecular structure and
physiological function of chloride channels. Physiol. Rev. v. 82 p. 503–568.
Research
Accardi, A., and Miller, C., 2004. Secondary active transport mediated by a prokaryotic
homologue of ClC Cl- channels. Nature v. 427 p. 803–807.
Birkenhäger, R., et al., 2001. Mutation of BSND causes Bartter syndrome with
sensorineural deafness and kidney failure. Nat. Genet. v. 29 p. 310–314.
Dutzler, R., Campbell, E. B., and MacKinnon, R., 2003. Gating the selectivity filter in
ClC chloride channels. Science v. 300 p. 108–112.
Dutzler, R., Campbell, E. B., Cadene, M., Chait, B. T., and MacKinnon, R., 2002. X-ray
structure of a ClC chloride channel at 3.0 Å reveals the molecular basis of anion
selectivity. Nature v. 415 p. 287–294.
Koch, M. C., Steinmeyer, K., Lorenz, C., Ricker, K., Wolf, F., Otto, M., Zoll, B.,
Lehmann-Horn, F., Grzeschik, K. H., and Jentsch, T. J., 1992. The skeletal
muscle chloride channel in dominant and recessive human myotonia. Science v.
257 p. 797–800.
Kornak, U., Kasper, D., Bösl, M. R., Kaiser, E., Schweizer, M., Schulz, A., Friedrich, W.,
Delling, G., and Jentsch, T. J., 2001. Loss of the ClC-7 chloride channel leads to
osteopetrosis in mice and man. Cell v. 104 p. 205–215.
Lloyd, S. E., et al., 1996. A common molecular basis for three inherited kidney stone
diseases. Nature v. 379 p. 445–449.
Miller, C., and White, M. M., 1984. Dimeric structure of single chloride channels from
Torpedo electroplax. Proc. Natl. Acad. Sci. USA v. 81 p. 2772–2775.
Pusch, M., Ludewig, U., Rehfeldt, A., and Jentsch, T. J., 1995. Gating of the voltagedependent chloride channel CIC-0 by the permeant anion. Nature v. 373 p. 527–
531.
Simon, D. B., et al., 1997. Mutations in the chloride channel gene, CLCNKB, cause
Bartter’s syndrome type III. Nat. Genet. v. 17 p. 171–178.
6.11 Selective water transport occurs through aquaporin channels
Review
Lehmann, G. L., Gradilone, S. A., and Marinelli, R. A., 2004. Aquaporin water channels
in central nervous system. Curr. Neurovasc. Res. v. 1 p. 293–303.
Nielsen, S., Frøkiaer, J., Marples, D., Kwon, T. H., Agre, P., and Knepper, M. A., 2002.
Aquaporins in the kidney: from molecules to medicine. Physiol. Rev. v. 82 p.
205–244.
Valenti, G., Procino, G., Tamma, G., Carmosino, M., and Svelto, M., 2005. Minireview:
aquaporin 2 trafficking. Endocrinology v. 146 p. 5063–5070.
Verkman, A. S., 2005. More than just water channels: unexpected cellular roles of
aquaporins. J. Cell Sci. v. 118 p. 3225–3232.
Research
Deen, P. M., Verdijk, M. A., Knoers, N. V., Wieringa, B., Monnens, L. A., van Os, C. H.,
and van Oost, B. A., 1994. Requirement of human renal water channel aquaporin2 for vasopressin-dependent concentration of urine. Science v. 264 p. 92–95.
Harries, W. E., Akhavan, D., Miercke, L. J., Khademi, S., and Stroud, R. M., 2004. The
channel architecture of aquaporin-0 at a 2.2-Å resolution. Proc. Natl. Acad. Sci.
USA v. 101 p. 14045–14050.
Jung, J. S., Preston, G. M., Smith, B. L., Guggino, W. B., and Agre, P., 1994. Molecular
structure of the water channel through aquaporin CHIP. The hourglass model. J.
Biol. Chem. v. 269 p. 14648–14654.
King, L. S., Choi, M., Fernandez, P. C., Cartron, J. P., and Agre, P., 2001. Defective
urinary-concentrating ability due to a complete deficiency of aquaporin-1. N.
Engl. J. Med. v. 345 p. 175–179.
Murata, K., Mitsuoka, K., Hirai, T., Walz, T., Agre, P., Heymann, J. B., Engel, A., and
Fujiyoshi, Y., 2000. Structural determinants of water permeation through
aquaporin-1. Nature v. 407 p. 599–605.
Smith, B. L., and Agre, P., 1991. Erythrocyte Mr 28,000 transmembrane protein exists as
a multisubunit oligomer similar to channel proteins. J. Biol. Chem. v. 266 p.
6407–6415.
Sui, H., Han, B. G., Lee, J. K., Walian, P., and Jap, B. K., 2001. Structural basis of
water-specific transport through the AQP1 water channel. Nature v. 414 p. 872–
878.
Zeidel, M. L., Ambudkar, S. V., Smith, B. L., and Agre, P., 1992. Reconstitution of
functional water channels in liposomes containing purified red cell CHIP28
protein. Biochemistry v. 31 p. 7436–7440.
6.12 Action potentials are electrical signals that depend on several types of ion channels
Review
Carmeliet, E., 2004. Intracellular Ca(2+) concentration and rate adaptation of the cardiac
action potential. Cell Calcium v. 35 p. 557–573.
Keating, M. T., and Sanguinetti, M. C., 2001. Molecular and cellular mechanisms of
cardiac arrhythmias. Cell v. 104 p. 569–580.
Nichols, C. G., and Lopatin, A. N., 1997. Inward rectifier potassium channels. Annu. Rev.
Physiol. v. 59 p. 171–191.
Sah, R., Ramirez, R. J., Oudit, G. Y., Gidrewicz, D., Trivieri, M. G., Zobel, C., and
Backx, P. H., 2003. Regulation of cardiac excitation-contraction coupling by
action potential repolarization: role of the transient outward potassium current
(Ito). J. Physiol. v. 546 p. 5–18.
Research
Bennett, P. B., Yazawa, K., Makita, N., and George, A. L., 1995. Molecular mechanism
for an inherited cardiac arrhythmia. Nature v. 376 p. 683–685.
Chen, Q., et al., 1998. Genetic basis and molecular mechanism for idiopathic ventricular
fibrillation. Nature v. 392 p. 293–296.
Curran, M. E., Splawski, I., Timothy, K. W., Vincent, G. M., Green, E. D., and Keating,
M. T., 1995. A molecular basis for cardiac arrhythmia: HERG mutations cause
long QT syndrome. Cell v. 80 p. 795–803.
Hodgkin, A. L., and Huxley, A. F., 1952. A quantitative description of membrane current
and its application to conduction and excitation in nerve. J. Physiol. v. 117 p.
500–544.
Hodgkin, A. L. and Huxley, A. F., 1952. Propagation of electrical signals along giant
nerve fibers. Proc. R Soc. Lond. B Biol. Sci. v. 140 p. 177–183.
Hodgkin, A. L. and Huxley, A. F., 1952. Movement of sodium and potassium ions during
nervous activity. Cold Spring Harb. Symp. Quant. Biol. v. 17 p. 43–52.
Lossin, C., Wang, D. W., Rhodes, T. H., Vanoye, C. G., and George, A. L., 2002.
Molecular basis of an inherited epilepsy. Neuron v. 34 p. 877–884.
Schott, J. J., Alshinawi, C., Kyndt, F., Probst, V., Hoorntje, T. M., Hulsbeek, M., Wilde,
A. A., Escande, D., Mannens, M. M., and Le Marec, H., 1999. Cardiac
conduction defects associate with mutations in SCN5A. Nat. Genet. v. 23 p. 20–
21.
Splawski, I., et al., 2004. Ca(V)1.2 calcium channel dysfunction causes a multisystem
disorder including arrhythmia and autism. Cell v. 119 p. 19–31.
Wang, Q., Shen, J., Splawski, I., Atkinson, D., Li, Z., Robinson, J. L., Moss, A. J.,
Towbin, J. A., and Keating, M. T., 1995. SCN5A mutations associated with an
inherited cardiac arrhythmia, long QT syndrome. Cell v. 80 p. 805–811.
6.13 Cardiac and skeletal muscles are activated by excitation-contraction coupling
Review
Berchtold, M. W., Brinkmeier, H., and Müntener, M., 2000. Calcium ion in skeletal
muscle: its crucial role for muscle function, plasticity, and disease. Physiol. Rev.
v. 80 p. 1215–1265.
Berridge, M. J., Bootman, M. D., and Roderick, H. L., 2003. Calcium signalling:
dynamics, homeostasis and remodelling. Nat. Rev. Mol. Cell Biol. v. 4 p. 517–
529.
Bers, D. M., 2002. Cardiac excitation-contraction coupling. Nature v. 415 p. 198–205.
da Fonseca, P. C., Morris, S. A., Nerou, E. P., Taylor, C. W., and Morris, E. P., 2003.
Domain organization of the type 1 inositol 1,4,5-trisphosphate receptor as
revealed by single-particle analysis Proc. Natl. Acad. Sci. USA v. 100 p. 3936–
3941.
Rizzuto, R., and Pozzan, T., 2006. Microdomains of intracellular Ca2+: molecular
determinants and functional consequences. Physiol. Rev. v. 86 p. 369–408.
Wehrens, X. H., Lehnart, S. E., and Marks, A. R., 2005. Intracellular calcium release and
cardiac disease. Annu. Rev. Physiol. v. 67 p. 69–98.
Research
Campbell, K. P., Knudson, C. M., Imagawa, T., Leung, A. T., Sutko, J. L., Kahl, S. D.,
Raab, C. R., and Madson, L., 1987. Identification and characterization of the high
affinity [3H]ryanodine receptor of the junctional sarcoplasmic reticulum Ca2+
release channel. J. Biol. Chem. v. 262 p. 6460–6463.
Lehnart, S. E., Wehrens, X. H., Reiken, S., Warrier, S., Belevych, A. E., Harvey, R. D.,
Richter, W., Jin, S. L., Conti, M., and Marks, A. R., 2005. Phosphodiesterase 4D
deficiency in the ryanodine-receptor complex promotes heart failure and
arrhythmias. Cell v. 123 p. 25–35.
Marx, S. O., Reiken, S., Hisamatsu, Y., Jayaraman, T., Burkhoff, D., Rosemblit, N., and
Marks, R., 2000. PKA phosphorylation dissociates FKBP12.6 from the calcium
release channel (ryanodine receptor): defective regulation in failing hearts. Cell v.
101 p. 365–376.
Sharma, M. R., Penczek, P., Grassucci, R., Xin, H. B., Fleischer, S., and Wagenknecht,
T., 1998. Cryoelectron microscopy and image analysis of the cardiac ryanodine
receptor. J. Biol. Chem. v. 273 p. 18429–18434.
Tanabe, T., Beam, K. G., Adams, B. A., Niidome, T., and Numa, S., 1990. Regions of
the skeletal muscle dihydropyridine receptor critical for excitation-contraction
coupling. Nature v. 346 p. 567–569.
Wehrens, X. H., Lehnart, S. E., Reiken, S. R., Deng, S. X., Vest, J. A., Cervantes, D.,
Coromilas, J., Landry, D. W., and Marks, A. R., 2004. Protection from cardiac
arrhythmia through ryanodine receptor-stabilizing protein calstabin2. Science v.
304 p. 292–296.
Wehrens, X. H. et al., 2003. FKBP12.6 deficiency and defective calcium release channel
(ryanodine receptor) function linked to exercise-induced sudden cardiac death.
Cell v. 113 p. 829–840.
6.14 Some glucose transporters are uniporters
Review
Devaskar, S. U., and Mueckler, M. M., 1992. The mammalian glucose transporters.
Pediatr. Res. v. 31 p. 1–13.
Kahn, B. B., 1992. Facilitative glucose transporters: regulatory mechanisms and
dysregulation in diabetes. J. Clin. Invest. v. 89 p. 1367–1374.
Saier, M. H., 2000. Families of transmembrane sugar transport proteins. Mol. Microbiol.
v. 35 p. 699–710.
Vannucci, S. J., Maher, F., and Simpson, I. A., 1997. Glucose transporter proteins in
brain: delivery of glucose to neurons and glia. Glia v. 21 p. 2–21.
Research
Heilig, C. W., Saunders, T., Brosius, F. C., Moley, K., Heilig, K., Baggs, R., Guo, L., and
Conner, D., 2003. Glucose transporter-1-deficient mice exhibit impaired
development and deformities that are similar to diabetic embryopathy. Proc. Natl.
Acad. Sci. USA v. 100 p. 15613–15618.
Mueckler, M., Caruso, C., Baldwin, S. A., Panico, M., Blench, I., Morris, H. R., Allard,
W. J., Lienhard, G. E., and Lodish, H. F., 1985. Sequence and structure of a
human glucose transporter. Science v. 229 p. 941–945.
Mueckler, M., and Makepeace, C., 2004. Analysis of transmembrane segment 8 of the
GLUT1 glucose transporter by cysteine-scanning mutagenesis and substituted
cysteine accessibility. J. Biol. Chem. v. 279 p. 10494–10499.
Seidner, G., Alvarez, M. G., Yeh, J. I., O’Driscoll, K. R., Klepper, J., Stump, T. S.,
Wang, D., Spinner, N. B., Birnbaum, M. J., and De Vivo, D. C., 1998. GLUT-1
deficiency syndrome caused by haploinsufficiency of the blood-brain barrier
hexose carrier. Nat. Genet. v. 18 p. 188–191.
Shigematsu, S., Watson, R. T., Khan, A. H., and Pessin, J. E., 2003. The adipocyte
plasma membrane caveolin functional/structural organization is necessary for the
efficient endocytosis of GLUT4. J. Biol. Chem. v. 278 p. 10683–10690.
6.15 Symporters and antiporters mediate coupled transport
Review
Abramson, J., Smirnova, I., Kasho, V., Verner, G., Iwata, S., and Kaback, H. R., 2003.
The lactose permease of Escherichia coli: overall structure, the sugar-binding site
and the alternating access model for transport. FEBS Lett. v. 555 p. 96–101.
Kaback, H. R., Sahin-Tóth, M., and Weinglass, A. B., 2001. The kamikaze approach to
membrane transport. Nat. Rev. Mol. Cell Biol. v. 2 p. 610–620.
Research
Abramson, J., Smirnova, I., Kasho, V., Verner, G., Kaback, H. R., and Iwata, S., 2003.
Structure and mechanism of the lactose permease of Escherichia coli. Science v.
301 p. 610–615.
Huang, Y., Lemieux, M. J., Song, J., Auer, M., and Wang, D. N., 2003. Structure and
mechanism of the glycerol-3-phosphate transporter from Escherichia coli. Science
v. 301 p. 616–620.
Jardetzky, O., 1966. Simple allosteric model for membrane pumps. Nature v. 211 p. 969–
970.
6.16 The transmembrane Na+ gradient is essential for the function of many transporters
Review
Blaustein, M. P., and Lederer, W. J., 1999. Sodium/calcium exchange: its physiological
implications. Physiol. Rev. v. 79 p. 763–854.
Ellison, D. H., 2000. Divalent cation transport by the distal nephron: insights from
Bartter’s and Gitelman’s syndromes. Am. J. Physiol. Renal Physiol. v. 279 p.
F616–F625.
Kaplan, M. R., Mount, D. B., and Delpire, E., 1996. Molecular mechanisms of NaCl
cotransport. Annu. Rev. Physiol. v. 58 p. 649–668.
Rasgado-Flores, H., and Gonzalez-Serratos, H., 2000. Plasmalemmal transport of
magnesium in excitable cells. Front. Biosci. v. 5 p. D866–D879.
Webel, R., Haug-Collet, K., Pearson, B., Szerencsei, R. T., Winkfein, R. J., Schnetkamp,
P. P., and Colley, N. J., 2002. Potassium-dependent sodium-calcium exchange
through the eye of the fly. Ann. N Y Acad. Sci. v. 976 p. 300–314.
Research
Haug-Collet, K., Pearson, B., Webel, R., Szerencsei, R. T., Winkfein, R. J., Schnetkamp,
P. P., and Colley, N. J., 1999. Cloning and characterization of a potassiumdependent sodium/calcium exchanger in Drosophila. J. Cell Biol. v. 147 p. 659–
670.
Nicoll, D. A., Ottolia, M., Lu, L., Lu, Y., and Philipson, K. D., 1999. A new topological
model of the cardiac sarcolemmal Na+-Ca2+ exchanger. J. Biol. Chem. v. 274 p.
910–917.
Simon, D. B., Karet, F. E., Hamdan, J. M., DiPietro, A., Sanjad, S. A., and Lifton, R. P.,
1996. Bartter’s syndrome, hypokalaemic alkalosis with hypercalciuria, is caused
by mutations in the Na-K-2Cl cotransporter NKCC2. Nat. Genet. v. 13 p. 183–
188.
Simon, D. B., Karet, F. E., Rodriguez-Soriano, J., Hamdan, J. H., DiPietro, A.,
Trachtman, H., Sanjad, S. A., and Lifton, R. P., 1996. Genetic heterogeneity of
Bartter’s syndrome revealed by mutations in the K+ channel, ROMK. Nat. Genet.
v. 14 p. 152–156.
Simon, D. B., et al., 1997. Mutations in the chloride channel gene, CLCNKB, cause
Bartter’s syndrome type III. Nat. Genet. v. 17 p. 171–178.
Simon, D. B., et al., 1996. Gitelman’s variant of Bartter’s syndrome, inherited
hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl
cotransporter. Nat. Genet. v. 12 p. 24–30.
6.17 Some Na+ transporters regulate cytosolic or extracellular pH
Review
Bobulescu, I. A., Di Sole, F., and Moe, O. W., 2005. Na+/H+ exchangers: physiology and
link to hypertension and organ ischemia. Curr. Opin. Nephrol. Hypertens. v. 14 p.
485–494.
Fliegel, L., and Karmazyn, M., 2004. The cardiac Na-H exchanger: a key downstream
mediator for the cellular hypertrophic effects of paracrine, autocrine and
hormonal factors. Biochem. Cell Biol. v. 82 p. 626–635.
Gross, E., and Kurtz, I., 2002. Structural determinants and significance of regulation of
electrogenic Na+-HCO3– cotransporter stoichiometry. Am. J. Physiol. Renal
Physiol. v. 283 p. F876–F887.
Wakabayashi, S., Shigekawa, M., and Pouyssegur, J., 1997. Molecular physiology of
vertebrate Na+/H+ exchangers. Physiol. Rev. v. 77 p. 51–74.
Zachos, N. C., Tse, M., and Donowitz, M., 2005. Molecular physiology of intestinal
Na+/H+ exchange. Annu. Rev. Physiol. v. 67 p. 411–443.
Research
Akiba, Y., Furukawa, O., Guth, P. H., Engel, E., Nastaskin, I., Sassani, P., Dukkipatis, R.,
Pushkin, A., Kurtz, I., and Kaunitz, J. D., 2001. Cellular bicarbonate protects rat
duodenal mucosa from acid-induced injury. J. Clin. Invest. v. 108 p. 1807–1816.
Hunte, C., Screpanti, E., Venturi, M., Rimon, A., Padan, E., and Michel, H., 2005.
Structure of a Na+/H+ antiporter and insights into mechanism of action and
regulation by pH. Nature v. 435 p. 1197–1202.
Orlowski, J. and Grinstein, S., 2004. Diversity of the mammalian sodium/proton
exchanger SLC9 gene family. Pflugers Arch. v. 447 p. 549–565.
Williams, K. A., 2000. Three-dimensional structure of the ion-coupled transport protein
NhaA. Nature v. 403 p. 112–115.
6.18 The Ca2+-ATPase pumps Ca2+ into intracellular storage compartments
Review
Belke, D. D., and Dillmann, W. H., 2004. Altered cardiac calcium handling in diabetes.
Curr. Hypertens. Rep. v. 6 p. 424–429.
Green, N. M., and MacLennan, D. H., 2002. Calcium callisthenics. Nature v. 418 p. 598–
599.
Kühlbrandt, W., 2004. Biology, structure and mechanism of P-type ATPases. Nat. Rev.
Mol. Cell Biol. v. 5 p. 282–295.
Laporte, R., Hui, A., and Laher, I., 2004. Pharmacological modulation of sarcoplasmic
reticulum function in smooth muscle. Pharmacol. Rev. v. 56 p. 439–513.
Stokes, D. L., and Green, N. M., 2003. Structure and function of the calcium pump.
Annu. Rev. Biophys. Biomol. Struct. v. 32 p. 445–468.
Strehler, E. E., and Treiman, M., 2004. Calcium pumps of plasma membrane and cell
interior. Curr. Mol. Med. v. 4 p. 323–335.
Sweadner, K. J., and Donnet, C., 2001. Structural similarities of Na,K-ATPase and
SERCA, the Ca2+-ATPase of the sarcoplasmic reticulum. Biochem. J. v. 356 p.
685–704.
Verkhratsky, A., 2004. Endoplasmic reticulum calcium signaling in nerve cells. Biol. Res.
v. 37 p. 693–699.
Research
Sørensen, T. L., Møller, J. V., and Nissen, P., 2004. Phosphoryl transfer and calcium ion
occlusion in the calcium pump. Science v. 304 p. 1672–1675.
Toyoshima, C., Nakasako, M., Nomura, H., and Ogawa, H., 2000. Crystal structure of
the calcium pump of sarcoplasmic reticulum at 2.6 Å resolution. Nature v. 405 p.
647–655.
Toyoshima, C., and Nomura, H., 2002. Structural changes in the calcium pump
accompanying the dissociation of calcium. Nature v. 418 p. 605–611.
6.19 The Na+/K+-ATPase maintains the plasma membrane Na+ and K+ gradients
Review
Glitsch, H. G., 2001. Electrophysiology of the sodium-potassium-ATPase in cardiac
cells. Physiol. Rev. v. 81 p. 1791–1826.
Horisberger, J. D., 2004. Recent insights into the structure and mechanism of the sodium
pump. Physiology (Bethesda) v. 19 p. 377–387.
Kühlbrandt, W., 2004. Biology, structure and mechanism of P-type ATPases. Nat. Rev.
Mol. Cell Biol. v. 5 p. 282–295.
Rakowski, R. F., and Sagar, S., 2003. Found: Na+ and K+ binding sites of the sodium
pump. News Physiol. Sci. v. 18 p. 164–168.
Sweadner, K. J., and Donnet, C., 2001. Structural similarities of Na,K-ATPase and
SERCA, the Ca2+-ATPase of the sarcoplasmic reticulum. Biochem. J. v. 356 p.
685–704.
Research
Hilge, M., Siegal, G., Vuister, G. W., Güntert, P., Gloor, S. M., and Abrahams, J. P.,
2003. ATP-induced conformational changes of the nucleotide-binding domain of
Na,K-ATPase. Nat. Struct. Biol. v. 10 p. 468–474.
Rice, W. J., Young, H. S., Martin, D. W., Sachs, J. R., and Stokes, D. L., 2001. Structure
of Na+,K+-ATPase at 11-Å resolution: comparison with Ca2+-ATPase in E1 and E2
states. Biophys. J. v. 80 p. 2187–2197.
Toyoshima, C., and Nomura, H., 2002. Structural changes in the calcium pump
accompanying the dissociation of calcium. Nature v. 418 p. 605–611.
6.20 The F1Fo-ATP synthase couples H+ movement to ATP synthesis or hydrolysis
Review
Senior, A. E., Nadanaciva, S., and Weber, J., 2002. The molecular mechanism of ATP
synthesis by F1Fo-ATP synthase. Biochim. Biophys. Acta v. 1553 p. 188–211.
Research
Bernal, R. A. and Stock, D., 2004. Three-dimensional structure of the intact Thermus
thermophilus H+-ATPase/synthase by electron microscopy. Structure (Camb) v.
12 p. 1789–1798.
Itoh, H., Takahashi, A., Adachi, K., Noji, H., Yasuda, R., Yoshida, M., and Kinosita, K.,
2004. Mechanically driven ATP synthesis by F1-ATPase. Nature v. 427 p. 465–
468.
Senior, A. E. and Weber, J., 2004. Happy motoring with ATP synthase. Nat. Struct. Mol.
Biol. v. 11 p. 110–112.
Stock, D., Leslie, A. G., and Walker, J. E., 1999. Molecular architecture of the rotary
motor in ATP synthase. Science v. 286 p. 1700–1705.
6.21 H+-ATPases transport protons out of the cytosol
Review
Bajjalieh, S., 2005. A new view of an old pore. Cell v. 121 p. 496–497.
Brown, D., and Breton, S., 2000. H(+)V-ATPase-dependent luminal acidification in the
kidney collecting duct and the epididymis/vas deferens: vesicle recycling and
transcytotic pathways. J. Exp. Biol. v. 203 p. 137–145.
Fillingame, R. H., Jiang, W., and Dmitriev, O. Y., 2000. Coupling H(+) transport to
rotary catalysis in F-type ATP synthases: structure and organization of the
transmembrane rotary motor. J. Exp. Biol. v. 203 Pt 1 p. 9–17.
Grüber, G., Wieczorek, H., Harvey, W. R., and Müller, V., 2001. Structure-function
relationships of A-, F- and V-ATPases. J. Exp. Biol. v. 204 p. 2597–2605.
Karet, F. E., 2002. Monogenic tubular salt and acid transporter disorders. J.
Nephrol. v. 15 Suppl 6 p. S57–S68.
Nishi, T., and Forgac, M., 2002. The vacuolar (H+)-ATPases—nature’s most versatile
proton pumps. Nat. Rev. Mol. Cell Biol. v. 3 p. 94–103.
Stevens, T. H., and Forgac, M., 1997. Structure, function and regulation of the vacuolar
(H+)-ATPase. Annu. Rev. Cell Dev. Biol. v. 13 p. 779–808.
Vik, S. B., Long, J. C., Wada, T., and Zhang, D., 2000. A model for the structure of
subunit a of the Escherichia coli ATP synthase and its role in proton translocation.
Biochim. Biophys. Acta v. 1458 p. 457–466.
Research
Arai, H., Terres, G., Pink, S., and Forgac, M., 1988. Topography and subunit
stoichiometry of the coated vesicle proton pump. J. Biol. Chem. v. 263 p. 8796–
8802.
Kane, P. M., 1995. Disassembly and reassembly of the yeast vacuolar H+-ATPase in
vivo. J. Biol. Chem. v. 270 p. 17025–17032.
Smith, A. N., Lovering, R. C., Futai, M., Takeda, J., Brown, D., and Karet, F. E., 2003.
Revised nomenclature for mammalian vacuolar-type H+-ATPase subunit genes.
Mol. Cell v. 12 p. 801–803.
Vasilyeva, E., Liu, Q., MacLeod, K. J., Baleja, J. D., and Forgac, M., 2000. Cysteine
scanning mutagenesis of the noncatalytic nucleotide binding site of the yeast VATPase. J. Biol. Chem. v. 275 p. 255–260.
Wilkens, S., Vasilyeva, E., and Forgac, M., 1999. Structure of the vacuolar ATPase by
electron microscopy. J. Biol. Chem. v. 274 p. 31804–31810.
6.22 What’s next?
Review
Multiple authors, 2004. The state of ion channel research in 2004. Nat. Rev. Drug Discov.
v. 3 p. 239–278.
6.25 Supplement: Most K+ channels undergo rectification
Review
Ashcroft, F. M., 1988. Adenosine 5’-triphosphate-sensitive potassium channels. Annu.
Rev. Neurosci. v. 11 p. 97–118.
Ashcroft, F. M., and Gribble, F. M., 1999. ATP-sensitive K+ channels and insulin
secretion: their role in health and disease. Diabetologia v. 42 p. 903–919.
Bichet, D., Haass, F. A., and Jan, L. Y., 2003. Merging functional studies with structures
of inward-rectifier K+ channels. Nat. Rev. Neurosci. v. 4 p. 957–967.
Campbell, J. D., Sansom, M. S., and Ashcroft, F. M., 2003. Potassium channel
regulation. EMBO Rep. v. 4 p. 1038–1042.
Dhamoon, A. S., and Jalife, J., 2005. The inward rectifier current (IK1) controls cardiac
excitability and is involved in arrhythmogenesis. Heart Rhythm v. 2 p. 316–324.
Lu, Z., 2004. Mechanism of rectification in inward-rectifier K+ channels. Annu. Rev.
Physiol. v. 66 p. 103–129.
Nichols, C. G., and Lopatin, A. N., 1997. Inward rectifier potassium channels. Annu. Rev.
Physiol. v. 59 p. 171–191.
Research
Kuo, A., Gulbis, J. M., Antcliff, J. F., Rahman, T., Lowe, E. D., Zimmer, J., Cuthbertson,
J., Ashcroft, F. M., Ezaki, T., and Doyle, D. A., 2003. Crystal structure of the
potassium channel KirBac1.1 in the closed state. Science v. 300 p. 1922–1926.
Liu, Y., Jurman, M. E., and Yellen, G., 1996. Dynamic rearrangement of the outer mouth
of a K+ channel during gating. Neuron v. 16 p. 859–867.
Reimann, F., Huopio, H., Dabrowski, M., Proks, P., Gribble, F. M., Laakso, M.,
Otonkoski, T., and Ashcroft, F. M., 2003. Characterisation of new KATP-channel
mutations associated with congenital hyperinsulinism in the Finnish population.
Diabetologia v. 46 p. 241–249.
6.26 Supplement: Mutations in an anion channel cause cystic fibrosis
Review
Higgins, C. F., 2001. ABC transporters: physiology, structure and mechanism—an
overview. Res. Microbiol. v. 152 p. 205–210.
Riordan, J. R., 2005. Assembly of functional CFTR chloride channels. Annu. Rev.
Physiol. v. 67 p. 701–718.
Sheppard, D. N., and Welsh, M. J., 1999. Structure and function of the CFTR chloride
channel. Physiol. Rev. v. 79 p. S23–S45.
Slieker, M. G., Sanders, E. A., Rijkers, G. T., Ruven, H. J., and van der Ent, C. K., 2005.
Disease modifying genes in cystic fibrosis. J. Cyst. Fibros. v. 4 Suppl 2 p. 7–13.
Steward, M. C., Ishiguro, H., and Case, R. M., 2005. Mechanisms of bicarbonate
secretion in the pancreatic duct. Annu. Rev. Physiol. v. 67 p. 377–409.
Research
Bear, C. E., Li, C. H., Kartner, N., Bridges, R. J., Jensen, T. J., Ramjeesingh, M., and
Riordan, J. R., 1992. Purification and functional reconstitution of the cystic
fibrosis transmembrane conductance regulator (CFTR). Cell v. 68 p. 809–818.
Bishop, L., Agbayani, R., Ambudkar, S. V., Maloney, P. C., and Ames, G. F., 1989.
Reconstitution of a bacterial periplasmic permease in proteoliposomes and
demonstration of ATP hydrolysis concomitant with transport. Proc. Natl. Acad.
Sci. USA v. 86 p. 6953–6957.
Chang, G., and Roth, C. B., 2001. Structure of MsbA from E. coli: a homolog of the
multidrug resistance ATP binding cassette (ABC) transporters. Science v. 293 p.
1793–1800.
Knowles, M. R., Stutts, M. J., Spock, A., Fischer, N., Gatzy, J. T., and Boucher, R. C.,
1983. Abnormal ion permeation through cystic fibrosis respiratory epithelium.
Science v. 221 p. 1067–1070.
Mall, M., Grubb, B. R., Harkema, J. R., O’Neal, W. K., and Boucher, R. C., 2004.
Increased airway epithelial Na+ absorption produces cystic fibrosis-like lung
disease in mice. Nat. Med. v. 10 p. 487–493.
Quinton, P. M., 1983. Chloride impermeability in cystic fibrosis. Nature v. 301 p. 421–
422.
Randak, C., and Welsh, M. J., 2003. An intrinsic adenylate kinase activity regulates
gating of the ABC transporter CFTR. Cell v. 115 p. 837–850.
Reddy, M. M., Light, M. J., and Quinton, P. M., 1999. Activation of the epithelial Na+
channel (ENaC) requires CFTR Cl- channel function. Nature v. 402 p. 301–304.
Reddy, M. M., and Quinton, P. M., 2003. Control of dynamic CFTR selectivity by
glutamate and ATP in epithelial cells. Nature v. 423 p. 756–760.
Riordan, J. R., Rommens, J. M., Kerem, B., Alon, N., Rozmahel, R., Grzelczak, Z.,
Zielenski, J., Lok, S., Plavsic, N., and Chou, J. L., 1989. Identification of the
cystic fibrosis gene: cloning and characterization of complementary DNA.
Science v. 245 p. 1066–1073.
Wang, X. F., et al., 2003. Involvement of CFTR in uterine bicarbonate secretion and the
fertilizing capacity of sperm. Nat. Cell Biol. v. 5 p. 902–906.