Pflügers Archiv

, Volume 447, Issue 5, pp 683–688 | Cite as

The SLC24 Na+/Ca2+-K+ exchanger family: vision and beyond

The ABC of Solute carriers Guest Editor: Matthias A. Hediger


Na+/Ca2+-K+ exchange (NCKX) was first discovered in the outer segments of vertebrate rod photoreceptors (ROS), where it is the only mechanism for extruding the Ca2+ that enters ROS via the light-sensitive and cGMP-gated channels. ROS NCKX1 is the only NCKX gene family member studied extensively in situ. ROS NCKX1 cDNAs have been cloned subsequently from a number of species including man and shown to be the first member of a new gene family (SLCA24). Three further members of the human NCKX gene family have been cloned subsequently (NCKX24) by homology with NCKX1, while a partial sequence of a fifth human NCKX gene has appeared in the data base. NCKX-related genes have also been identified in lower animals including fruit flies, worms and sea urchins. NCKX2 is expressed in the brain, in retinal cone photoreceptors and in retinal ganglion cells, while NCKX3 and NCKX4 show a broader expression pattern. In situ NCKX1 and heterologously expressed NCKX2 operate at a 4Na+:1Ca2++1 K+ stoichiometry; both NCKX1 and NCKX2 are bidirectional transporters normally extruding Ca2+ from the cell (forward exchange), but also able to carry Ca2+ into the cell (reverse exchange) when the transmembrane Na+ gradient is reversed. Sequence changes have been observed for both NCKX1 and NCKX2 in patients with retinal diseases, but a definitive association with retinal disease has not been shown.


Calcium homeostasis Sodium-calcium exchange Sodium-calcium-potassium exchange Vision Rod photoreceptors Cone photoreceptors 


  1. 1.
    Cai X, Zhang K, Lytton J (2002) A novel topology and redox regulation of the rat brain K+-dependent Na+/Ca2+ exchanger, NCKX2. J Biol Chem 277:48923–48930CrossRefPubMedGoogle Scholar
  2. 2.
    Cervetto L, Lagnado L, Perry RJ, Robinson DW, McNaughton PA (1989) Extrusion of calcium from rod outer segments is driven by both sodium and potassium gradients. Nature 337:740–743PubMedGoogle Scholar
  3. 3.
    Cook NJ, Kaupp UB (1988) Solubilization, purification, and reconstitution of the sodium-calcium exchanger from bovine retinal rod outer segments. J Biol Chem 263:11382–11388PubMedGoogle Scholar
  4. 4.
    Cooper CB, Winkfein RJ, Szerencsei RT, Schnetkamp PPM (1999) cDNA-cloning and functional expression of the dolphin retinal rod Na-Ca+K exchanger NCKX1: comparison with the functionally silent bovine NCKX1. Biochemistry 38:6276–6283CrossRefPubMedGoogle Scholar
  5. 5.
    Dong H, Light PE, French RJ, Lytton J (2001) Electrophysiological characterization and ionic stoichiometry of the rat brain K+-dependent Na+/Ca2+ exchanger, NCKX2. J Biol Chem 276:25919–25928CrossRefPubMedGoogle Scholar
  6. 6.
    Fain GL, Matthews HR, Cornwall MC, Koutalos Y (2001) Adaptation in vertebrate photoreceptors. Physiol Rev 81:117–151PubMedGoogle Scholar
  7. 7.
    Haug-Collet K, Pearson B, Park S, Webel S, Szerencsei RT, Winkfein RJ, Schnetkamp PPM, Colley NJ (1999) Cloning and Characterization of a potassium-dependent sodium/calcium exchanger in Drosophila. J Cell Biol 147:659–669CrossRefPubMedGoogle Scholar
  8. 8.
    Kang K-J, Bauer PJ, Kinjo TG, Szerencsei RT, Bönigk W, Winkfein RJ, Schnetkamp PPM (2003) Assembly of retinal rod or cone Na+/Ca2+-K+ exchangers oligomers with cGMP-gated channel subunits as probed with heterologously expressed cDNAs. Biochemistry 42:4593–4600CrossRefPubMedGoogle Scholar
  9. 9.
    Kaupp UB, Seifert R (2002) Cyclic nucleotide-gated ion channels. Physiol Rev 82:769–824PubMedGoogle Scholar
  10. 10.
    Kimura J, Jeanclos EM, Donnelly RJ, Lytton J, Reeves JP, Aviv A (1999) Physiological and molecular characterization of the Na+/Ca2+ exchanger in human platelets. Am J Physiol 277:H911–H917PubMedGoogle Scholar
  11. 11.
    Kinjo TG, Szerencsei RT, Winkfein RJ, Kang K-J, Schnetkamp PPM (2003) Topology of the retinal cone NCKX2 Na/Ca-K exchanger. Biochemistry 42:2485–2491CrossRefPubMedGoogle Scholar
  12. 12.
    Kraev A, Quednau BD, Leach S, Li XF, Dong H, Winkfein RJ, Perizzolo M, Cai X, Yang R, Philipson KD, Lytton J (2001) Molecular cloning of a third member of the potassium-dependent sodium-calcium exchanger gene family, NCKX3. J Biol Chem 276:23161–23172CrossRefPubMedGoogle Scholar
  13. 13.
    Lagnado L, McNaughton PA (1990) Electrogenic properties of the Na:Ca exchange. J Membr Biol 113:177–191PubMedGoogle Scholar
  14. 14.
    Li XF, Kraev AS, Lytton J (2002) Molecular cloning of a fourth member of the potassium-dependent sodium-calcium exchanger gene family, NCKX4. J Biol Chem 277:48410–48417CrossRefPubMedGoogle Scholar
  15. 15.
    Nicol GD, Schnetkamp PPM, Saimi Y, Cragoe EJ Jr, Bownds MD (1987) A derivative of amiloride blocks both the light- and cyclic GMP-regulated conductances in rod photoreceptors. J Gen Physiol 90:651–669PubMedGoogle Scholar
  16. 16.
    Poetsch A, Molday LL, Molday RS (2001) The cGMP-gated channel and related glutamic acid-rich proteins interact with peripherin-2 at the rim region of rod photoreceptor disc membranes. J Biol Chem 276:48009–48016PubMedGoogle Scholar
  17. 17.
    Poon S, Leach S, Li XF, Tucker JE, Schnetkamp PP, Lytton J (2000) Alternatively spliced isoforms of the rat eye sodium/calcium+potassium exchanger NCKX1. Am J Physiol 278:C651–C660Google Scholar
  18. 18.
    Prinsen CFM, Szerencsei RT, Schnetkamp PPM (2000) Molecular cloning and functional expression the potassium-dependent sodium-calcium exchanger from human and chicken retinal cone photoreceptors. J Neurosci 20:1424–1434PubMedGoogle Scholar
  19. 19.
    Reiländer H, Achilles A, Friedel U, Maul G, Lottspeich F, Cook NJ (1992) Primary structure and functional expression of the Na/Ca,K-exchanger from bovine rod photoreceptors. EMBO J 11:1689–1695PubMedGoogle Scholar
  20. 20.
    Sampath AP, Matthews HR, Cornwall MC, Fain GL (1998) Bleached pigment produces a maintained decrease in outer segment Ca2+ in salamander rods. J Gen Physiol 111:53–64CrossRefPubMedGoogle Scholar
  21. 21.
    Schnetkamp PPM (1986) Sodium-calcium exchange in the outer segments of bovine rod photoreceptors. J Physiol (Lond) 373:25–45Google Scholar
  22. 22.
    Schnetkamp PPM (1989) Na-Ca or Na-Ca-K exchange in the outer segments of vertebrate rod photoreceptors. Prog Biophys Mol Biol 54:1–29CrossRefPubMedGoogle Scholar
  23. 23.
    Schnetkamp PPM (1995) Calcium homeostasis in vertebrate retinal rod outer segments. Cell Calcium 18:322–330PubMedGoogle Scholar
  24. 24.
    Schnetkamp PPM (1995) How does the retinal rod Na-Ca + K exchanger regulate free cytosolic Ca2+? J Biol Chem 270:13231–13239Google Scholar
  25. 25.
    Schnetkamp PPM, Basu DK, Szerencsei RT (1989) Na-Ca exchange in the outer segments of bovine rod photoreceptors requires and transports potassium. Am J Physiol 257:C153–C157PubMedGoogle Scholar
  26. 26.
    Schnetkamp PPM, Basu DK, Li XB, Szerencsei RT (1991) Regulation of intracellular free Ca2+ concentration in the outer segments of bovine retinal rods by Na-Ca-K exchange measured with Fluo-3. II. Thermodynamic competence of transmembrane Na+ and K+ gradients and inactivation of Na+-dependent Ca2+ extrusion. J Biol Chem 266:22983–22990PubMedGoogle Scholar
  27. 27.
    Schnetkamp PPM, Basu DK, Szerencsei RT (1991) The stoichiometry of Na-Ca+K exchange in rod outer segments isolated from bovine retinas. Ann NY Acad Sci 639:10–21PubMedGoogle Scholar
  28. 28.
    Schwarz EM, Benzer S (1997) Calx, a Na-Ca exchanger gene of Drosophila melanogaster. Proc Natl Acad Sci USA 94:10249–10254CrossRefPubMedGoogle Scholar
  29. 29.
    Schwarzer A, Kim TSY, Hagen V, Molday RS, Bauer PJ (1997) The Na/Ca-K exchanger of rod photoreceptor exists as dimer in the plasma membrane. Biochemistry 36:13667–13676CrossRefPubMedGoogle Scholar
  30. 30.
    Schwarzer A, Schauf H, Bauer PJ (2000) Binding of the cGMP-gated channel to the Na/Ca-K exchanger in rod photoreceptors. J Biol Chem 275:13448–13454CrossRefPubMedGoogle Scholar
  31. 31.
    Sharon D, Yamamoto H, McGee TL, Rabe V, Szerencsei RT, Winkfein RJ, Prinsen CFM, Barnes CS, Andreasson S, Fishman GA, Schnetkamp PPM, Berson EL, Dryja TP (2002) Mutated alleles of the rod and cone Na/Ca+K exchanger genes in patients with retinal diseases. Invest Ophthalmol Vis Sci 43:1971–1979Google Scholar
  32. 32.
    Sheng J-Z, Prinsen CFM, Clark RB, Giles WR, Schnetkamp PPM (2000) Na+-Ca2+-K+ currents measured in insect cells transfected with the retinal cone or rod Na+-Ca2+-K+ exchanger cDNA. Biophys J 79:1945–1953PubMedGoogle Scholar
  33. 33.
    Su YH, Vacquier VD (2002) A flagellar K+-dependent Na+/Ca2+ exchanger keeps Ca2+ low in sea urchin spermatozoa. Proc Natl Acad Sci USA 99:6743–6748CrossRefPubMedGoogle Scholar
  34. 34.
    Szerencsei RT, Tucker JE, Cooper CB, Winkfein RJ, Farrell PJ, Iatrou K, Schnetkamp PPM (2000) Minimal domain requirement for cation transport by the potassium-dependent Na/Ca-K exchanger: comparison with an NCKX paralog from Caenorhabditis elegans. J Biol Chem 275:669–676CrossRefPubMedGoogle Scholar
  35. 35.
    Szerencsei RT, Prinsen CFM, Schnetkamp PPM (2001) The stoichiometry of the retinal cone Na/Ca-K exchanger heterologously expressed in insect cells: comparison with the bovine heart Na/Ca exchanger. Biochemistry 40:6009–6015CrossRefPubMedGoogle Scholar
  36. 36.
    Tsoi M, Rhee K-H, Bungard D, Li XB, Lee S-L, Auer RN, Lytton J (1998) Molecular cloning of a novel potassium-dependent sodium-calcium exchanger from rat brain. J Biol Chem 273:4155–4162CrossRefPubMedGoogle Scholar
  37. 37.
    Tucker JE, Winkfein RJ, Cooper CB, Schnetkamp PPM (1998) cDNA cloning of the human retinal rod Na-Ca+K exchanger: comparison with a revised bovine sequence. Invest Ophthalmol Vis Sci 39:435–440PubMedGoogle Scholar
  38. 38.
    Winkfein RJ, Szerencsei RT, Kinjo TG, Kang K-J, Perizzolo M, Eisner L, Schnetkamp PPM (2003) Scanning mutagenesis of the alpha repeats and of the transmembrane acidic residues of the human retinal cone Na/Ca-K exchanger. Biochemistry 42:543–552CrossRefPubMedGoogle Scholar
  39. 39.
    Yau K-W, Nakatani K (1984) Electrogenic Na-Ca exchange in retinal rod outer segment. Nature 311:661–663PubMedGoogle Scholar
  40. 40.
    Zhong H, Molday LL, Molday RS, Yau K-W (2002) The heteromeric cyclic nucleotide-gated channel adopts a 3A:1B stoichiometry. Nature 420:193–198CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag  2004

Authors and Affiliations

  1. 1.Department of Physiology and Biophysics, Faculty of MedicineUniversity of CalgaryN.W. CalgaryCanada

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