Journal of Molecular Evolution

, Volume 63, Issue 2, pp 208–221 | Cite as

Gene Duplications and Evolution of Vertebrate Voltage-Gated Sodium Channels

  • Alicia E. Novak
  • Manda C. Jost
  • Ying Lu
  • Alison D. Taylor
  • Harold H. Zakon
  • Angeles B. RiberaEmail author


Voltage-gated sodium channels underlie action potential generation in excitable tissue. To establish the evolutionary mechanisms that shaped the vertebrate sodium channel α-subunit (SCNA) gene family and their encoded Nav1 proteins, we identified all SCNA genes in several teleost species. Molecular cloning revealed that teleosts have eight SCNA genes, compared to ten in another vertebrate lineage, mammals. Prior phylogenetic analyses have indicated that the genomes of both teleosts and tetrapods contain four monophyletic groups of SCNA genes, and that tandem duplications expanded the number of genes in two of the four mammalian groups. However, the number of genes in each group varies between teleosts and tetrapods, suggesting different evolutionary histories in the two vertebrate lineages. Our findings from phylogenetic analysis and chromosomal mapping of Danio rerio genes indicate that tandem duplications are an unlikely mechanism for generation of the extant teleost SCNA genes. Instead, analyses of other closely mapped genes in D. rerio as well as of SCNA genes from several teleost species all support the hypothesis that a whole-genome duplication was involved in expansion of the SCNA gene family in teleosts. Interestingly, despite their different evolutionary histories, mRNA analyses demonstrated a conservation of expression patterns for SCNA orthologues in teleosts and tetrapods, suggesting functional conservation.


Voltage-gated sodium channel Teleosts Gene families Genome duplication Gene duplication 



The authors’ work was supported by NIH grants (NS 38937—A.E.N., A.D.T., and A.B.R.; NS 25513—H.H.Z. and Y.L.; and NSF IBN 0236147—M.C.J.).

Supplementary material

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Supplementary material


  1. Akopian AN, Sivilotti L, Wood JN (1996) A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. Nature 379:257–262PubMedGoogle Scholar
  2. Akopian AN, Souslova V, England S, Okuse K, Ogata N, Ure J, Smith A, Kerr BJ, McMahon SB, Boyce S, Hill R, Stanfa LC, Dickenson AH, Wood JN (1999) The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways. Nat Neurosci 2:541–548PubMedGoogle Scholar
  3. Amaya F, Decosterd I, Samad TA, Plumpton C, Tate S, Mannion RJ, Costigan M, Woolf CJ (2000) Diversity of expression of the sensory neuron-specific TTX-resistant voltage-gated sodium ion channels SNS and SNS2. Mol Cell Neurosci 15:331–342PubMedGoogle Scholar
  4. Amores A, Force A, Yan YL, Joly L, Amemiya C, Fritz A, Ho RK, Langeland J, Prince V, Wang YL, Westerfield M, Ekker M, Postlethwait JH (1998) Zebrafish hox clusters and vertebrate genome evolution. Science 282:1711–1714PubMedGoogle Scholar
  5. Ausubel F, Brent R, Kingston R, Moore D, Seidman J, Smith J, Struhl K (1994) Current protocols in molecular biology. Wiley, New YorkGoogle Scholar
  6. Catterall WA, Goldin AL, Waxman SG. (2005) Nomenclature and structure-function relationships of voltage-gated sodium channels. Pharmacol Rev 57:397–409PubMedGoogle Scholar
  7. Crow KD, Stadler PF, Lynch VT, Amemiya C, Wagner GP (2006) The “fish specific” Hox cluster duplication is coincident with the origin of teleosts. Mol Biol Evol 23:121–136PubMedGoogle Scholar
  8. de Souza FSJ, Bumaschny VF, Low MJ, Rubinstein M (2005) Subfunctionalization of expression and peptide domains following the ancient duplication of the Proopiomelanocortin gene in teleost fishes. Mol Biol Evol 22:2417–2427PubMedGoogle Scholar
  9. Dhar Malhotra J, Chen C, Rivolta I, Abriel H, Malhotra R, Mattei LN, Brosius FC, Kass RS, Isom LL (2001) Characterization of sodium channel alpha- and beta-subunits in rat and mouse cardiac myocytes. Circulation 103:1303–1310PubMedGoogle Scholar
  10. Dib-Hajj SD, Tyrrell L, Cummins TR, Black JA, Wood PM, Waxman SG (1999a) Two tetrodotoxin-resistant sodium channels in human dorsal root ganglion neurons. FEBS Lett 462:117–120Google Scholar
  11. Dib-Hajj SD, Tyrrell L, Escayg A, Wood PM, Meisler MH, Waxman SG (1999b) Coding sequence, genomic organization, and conserved chromosomal localization of the mouse gene SCN11A encoding the sodium channel NaN. Genomics 59:309–318Google Scholar
  12. Donahue LM, Coates PW, Lee VH, Ippensen DC, Arze SE, Poduslo SE (2000) The cardiac sodium channel mRNA is expressed in the developing and adult rat and human brain. Brain Res 887:335–343PubMedGoogle Scholar
  13. Ekker SC, Ungar AR, Greenstein P, von Kessler DP, Porter JA, Moon RT, Beachy PA (1995) Patterning activities of vertebrate hedgehog proteins in the developing eye and brain. Curr Biol 5:944–955PubMedGoogle Scholar
  14. Fatt P, Ginsborg BL (1958) The ionic requirements for the production of action potentials in crustacean muscle fibres. J Physiol 142:516–543PubMedGoogle Scholar
  15. Fried C, Prohaska SJ, Stadler PF (2003) Independent Hox-cluster duplications in lampreys. J Exp Zool B Mol Dev Evol 299:18–25PubMedGoogle Scholar
  16. George AL Jr, Iyer GS, Kleinfield R, Kallen RG, Barchi RL (1993) Genomic organization of the human skeletal muscle sodium channel gene. Genomics 15:598–606PubMedGoogle Scholar
  17. Goldin AL (2002) Evolution of voltage-gated Na(+) channels. J Exp Biol 205:575–584PubMedGoogle Scholar
  18. Goldin AL, Barchi RL, Caldwell JH, Hofmann F, Howe JR, Hunter JC, Kallen RG, Mandel G, Meisler MH, Netter YB, Noda M, Tamkun MM, Waxman SG, Wood JN, Catterall WA (2000) Nomenclature of voltage-gated sodium channels. Neuron 28:365–368PubMedGoogle Scholar
  19. Hagiwara S, Kidokoro Y (1971) Na and Ca components of action potential in amphioxus muscle cells. J Physiol 219:217–232PubMedGoogle Scholar
  20. Hartmann HA, Colom LV, Sutherland ML, Noebels JL (1999) Selective localization of cardiac SCN5A sodium channels in limbic regions of rat brain. Nat Neurosci 2:593–595PubMedGoogle Scholar
  21. Hoegg S, Brinkmann H, Taylor JS, Meyer A (2004) Phylogenetic timing of the fish-specific genome duplication correlates with the diversification of teleost fish. J Mol Evol 59:190–203PubMedGoogle Scholar
  22. Holland PW, Williams NA (1990) Conservation of engrailed-like homeobox sequences during vertebrate evolution. FEBS Lett 277:250–252PubMedGoogle Scholar
  23. Huelsenbeck JP, Ronquist F (2001) MRBAYES: Bayesian inference of phylogenetic trees. Bioinformatics 17:754–755PubMedGoogle Scholar
  24. Hukriede NA, Joly L, Tsang M, Miles J, Tellis P, Epstein JA, Barbazuk WB, Li FN, Paw B, Postlethwait JH, Hudson TJ, Zon LI, McPherson JD, Chevrette M, Dawid IB, Johnson SL, Ekker M (1999) Radiation hybrid mapping of the zebrafish genome. Proc Natl Acad Sci USA 96:9745–9750PubMedGoogle Scholar
  25. Jozefowicz C, McClintock J, Prince V (2003) The fates of zebrafish Hox gene duplicates. J Struct Funct Genomics 3:185–194PubMedGoogle Scholar
  26. Krzemien DM, Schaller KL, Levinson SR, Caldwell JH (2000) Immunolocalization of sodium channel isoform NaCh6 in the nervous system. J Comp Neurol 420:70–83PubMedGoogle Scholar
  27. Lopreato GF, Lu Y, Southwell A, Atkinson NS, Hillis DM, Wilcox TP, Zakon HH (2001) Evolution and divergence of sodium channel genes in vertebrates. Proc Natl Acad Sci USA 98:7588–7592PubMedGoogle Scholar
  28. Lundin LG (1993) Evolution of the vertebrate genome as reflected in paralogous chromosomal regions in man and the house mouse. Genomics 16:1–19PubMedGoogle Scholar
  29. Maddison WP, Maddison DR (1992) MacClade version 3: Analysis of phylogeny and character evolution. Sinauer Associates, Sunderland, MAGoogle Scholar
  30. Maier SK, Westenbroek RE, Schenkman KA, Feigl EO, Scheuer T, Catterall WA (2002) An unexpected role for brain-type sodium channels in coupling of cell surface depolarization to contraction in the heart. Proc Natl Acad Sci USA 99:4073–4078PubMedGoogle Scholar
  31. Meyer A, Schartl M (1999) Gene and genome duplications in vertebrates: the one-to-four (-to-eight in fish) rule and the evolution of novel gene functions. Curr Opin Cell Biol 11:699–704PubMedGoogle Scholar
  32. Novak AE, Taylor AD, Pineda RH, Lasada EL, Wright MA, Ribera AB (2006) Embryonic and larval expression of zebrafish voltage-gated sodium channel alpha-subunit genes. Dev Dyn 235:1962–1973PubMedGoogle Scholar
  33. Nylander JAA (2004) MrModeltest. Technical report. Evolutionary Biology Centre, Uppsala University, UniversityGoogle Scholar
  34. Ohno S (1970) Evolution by gene duplication. Springer-Verlag, BerlinGoogle Scholar
  35. Piontkivska H, Hughes AL (2003) Evolution of vertebrate voltage-gated ion channel alpha chains by sequential gene duplication. J Mol Evol 56:277–285PubMedGoogle Scholar
  36. Plummer NW, Meisler MH (1999) Evolution and diversity of mammalian sodium channel genes. Genomics 57:323–331PubMedGoogle Scholar
  37. Plummer NW, Galt J, Jones JM, Burgess DL, Sprunger LK, Kohrman DC, Meisler MH (1998) Exon organization, coding sequence, physical mapping, and polymorphic intragenic markers for the human neuronal sodium channel gene SCN8A. Genomics 54:287–296PubMedGoogle Scholar
  38. Prince V (2002) The Hox Paradox: more complex(es) than imagined. Dev Biol 249:1–15PubMedGoogle Scholar
  39. Rogart RB, Cribbs LL, Muglia LK, Kephart DD, Kaiser MW (1989) Molecular cloning of a putative tetrodotoxin-resistant rat heart Na+ channel isoform. Proc Natl Acad Sci USA 86:8170–8174PubMedGoogle Scholar
  40. Sambrook J, Fritsch EF, Maniatis T (1989) Molecular cloning: A laboratory manual. Cold Spring Harbor Laboratory, Cold Spring Harbor, NYGoogle Scholar
  41. Sangameswaran L, Delgado SG, Fish LM, Koch BD, Jakeman LB, Stewart GR, Sze P, Hunter JC, Eglen RM, Herman RC (1996) Structure and function of a novel voltage-gated, tetrodotoxin-resistant sodium channel specific to sensory neurons. J Biol Chem 271:5953–5956PubMedGoogle Scholar
  42. Schaller KL, Krzemien DM, Yarowsky PJ, Krueger BK, Caldwell JH (1995) A novel, abundant sodium channel expressed in neurons and glia. J Neurosci 15:3231–3242PubMedGoogle Scholar
  43. Sidow A (1996) Gen(om)e duplications in the evolution of early vertebrates. Curr Opin Genet Dev 6:715–722PubMedGoogle Scholar
  44. Sneddon LU, Braithwaite VA, Gentle MJ (2003) Do fishes have nociceptors? Evidence for the evolution of a vertebrate sensory system. Proc Biol Sci 270:1115–1121PubMedGoogle Scholar
  45. Souslova VA, Fox M, Wood JN, Akopian AN (1997) Cloning and characterization of a mouse sensory neuron tetrodotoxin-resistant voltage-gated sodium channel gene, Scn10a. Genomics 41:201–209PubMedGoogle Scholar
  46. Stadler PF, Fried C, Prohaska SJ, Bailey WJ, Misof BY, Ruddle FH, Wagner GP (2004) Evidence for independent Hox gene duplications in the hagfish lineage: a PCR-based gene inventory of Eptatretus stoutii. Mol Phylogenet Evol 32:686–694PubMedGoogle Scholar
  47. Stock DW, Ellies DL, Zhao Z, Ekker M, Ruddle FH, Weiss KM (1996) The evolution of the vertebrate Dlx gene family. Proc Natl Acad Sci USA 93:10858–10863PubMedGoogle Scholar
  48. Suzuki N, Kano M (1977) Development of action potential in larval muscle fibers in Drosophila melanogaster. J Cell Physiol 93:383–388PubMedGoogle Scholar
  49. Swofford DL (2002) PAUP* 4:40: Phylogenetic analysis using parsimony *and other methods. Sinauer Associates, Sunderland, MAGoogle Scholar
  50. Thompson JD, Higgins DG, Gibson TJ (1994) CLUSTAL W:improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res 22:4673–4680PubMedGoogle Scholar
  51. Trimmer JS, Cooperman SS, Tomiko SA, Zhou JY, Crean SM, Boyle MB, Kallen RG, Sheng ZH, Barchi RL, Sigworth FJ, Goodman RH, Agnew WS, Mandel G (1989) Primary structure and functional expression of a mammalian skeletal muscle sodium channel. Neuron 3:33–49PubMedGoogle Scholar
  52. Tsai CW, Tseng JJ, Lin SC, Chang CY, Wu JL, Horng JF, Tsay HJ (2001) Primary structure and developmental expression of zebrafish sodium channel Na(v)16 during neurogenesis. DNA Cell Biol 20:249–255PubMedGoogle Scholar
  53. Tzoumaka E, Tischler AC, Sangameswaran L, Eglen RM, Hunter JC, Novakovic SD (2000) Differential distribution of the tetrodotoxin-sensitive rPN4/NaCh6/Scn8a sodium channel in the nervous system. J Neurosci Res 60:37–44PubMedGoogle Scholar
  54. Vandepoele K, De Vos W, Taylor JS, Meyer A, Van de Peer Y (2004) Major events in the genome evolution of vertebrates: Paranome age and size differ considerably between ray-finned fishes and land vertebrates. Proc Natl Acad Sci USA 101:1638–1643PubMedGoogle Scholar
  55. Venkatesh B, Lu SQ, Dandona N, See SL, Brenner S, Soong TW (2005) Genetic basis of tetrodotoxin resistance in pufferfishes. Curr Biol 15:2069–2072PubMedGoogle Scholar
  56. Wang Q, Li Z, Shen J, Keating MT (1996) Genomic organization of the human SCN5A gene encoding the cardiac sodium channel. Genomics 34:9–16PubMedGoogle Scholar
  57. Westerfield M (1995) The zebrafish book: A guide for the laboratory use of zebrafish (Brachydanio rerio). University of Oregon Press, EugeneGoogle Scholar
  58. Wittbrodt J, Meyer A, Schartl A (1998) More genes in fish? BioEssays 20:511–515Google Scholar
  59. Zimmer T, Bollensdorff C, Haufe V, Birch-Hirschfeld E, Benndorf K (2002) Mouse heart Na+ channels: primary structure and function of two isoforms and alternatively spliced variants. Am J Physiol Heart Circ Physiol 282:H1007–H1017PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  • Alicia E. Novak
    • 1
  • Manda C. Jost
    • 2
    • 3
  • Ying Lu
    • 2
  • Alison D. Taylor
    • 1
  • Harold H. Zakon
    • 2
    • 4
  • Angeles B. Ribera
    • 1
    Email author
  1. 1.Department of Physiology and Biophysics, Mail Stop 8307, RC-1NUniversity of Colorado at Denver and Health Sciences CenterAuroraUSA
  2. 2.Section of NeurobiologyUniversity of Texas at AustinAustinUSA
  3. 3.Section of Integrative BiologyUniversity of Texas at AustinAustinUSA
  4. 4.The Josephine Bay Paul Center in Comparative and Molecular Biology and EvolutionMarine Biological LaboratoryWoods HoleUSA

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