Persistent Na-Channels: Origin and Function

A Review János Salánki Memory Lecture


Voltage-dependent sodium channels have a decisive role in the generation of action potentials (AP) in many types of cells. In addition to the fast inactivating Na-current, associated with AP generation, the Na-channel can give rise to a noninactivating or persistent Na-current. The latter current generally comprises up to 5% of the transient current having important physiological consequences. It was established that persistent Na-currents have functional significance in setting the membrane potential in a subthreshold range regulating by this way dendritic depolarisations, repetitive firing and enhancing synaptic transmission. Voltage dependent sodium channel genes have been identified in a variety of invertebrates, as well as mammalian and nonmammalian vertebrates. It has been established that the biophysical properties, pharmacology and gene organization of invertebrate sodium channels are largely similar to the vertebrate ones, supporting the view that the ancestral sodium channel was established before the evolutionary separation of the invertebrates from the vertebrates. Although different isoforms of voltage sensitive Na-channels have now been identified the mechanism for persistent current remains controversial. An important yet unanswered question is whether persistent and fast inactivating Na-currents arise from different sets of sodium channels or whether the persistent Na-current results from different gating of the same channel type. The aim of the present review is to discuss the origin and the function of the persistent current, focusing on data derived from an invertebrate animal.



action potential


persistent sodium current


fast inactivating sodium current


amino acid


dorsal root ganglion




voltage-dependent Nachannel


  1. 1.

    Agrawal, N., Hamam, B. N., Magistretti, J., Alonso, A., Ragsdale, D. S. (2001) Persistent sodium channel activity mediates subthreshold membrane potential oscillations and low-threshold spikes in rat entorhinal cortex layer V neurons. Neuroscienc. 102, 53–64.

    CAS  Google Scholar 

  2. 2.

    Akaike, H. (1974) A new look at the statistical model identification. IEEE Trans. Automatic Contro. 19, 716–723.

    Google Scholar 

  3. 3.

    Alzheimer, C., Schwindt, P. C., Crill, W. E. (1993) Modal gating of Na+ channels as a mechanism of persistent Na+ current in pyramidal neurons from rat and cat sensorimotor cortex. J. Neurosci. 13, 660–673.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Anderson, P. A. V. (1987) Properties and pharmacology of a TTX-insensitive Na+ current in neurons of the jellyfish Cyanea-Capillata. J. Exp. Biol. 133, 231–248.

    Google Scholar 

  5. 5.

    Angstadt, J. D. (1999) Persistent inward currents in cultured Retzius cells of the medicinal leech. J. Comp. Physiol. [A]. 184, 49–61.

    CAS  Google Scholar 

  6. 6.

    Armstrong, C. M., Bezanilla, F., Rojas, E. (1973) Destruction of sodium conductance inactivation in squid axons perfused with pronase. J. Gen. Physiol. 62, 375–391.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Brown, A. M., Schwindt, P. C., Crill, W. E. (1994) Different voltage dependence of transient and persistent Na+ currents is compatible with modal-gating hypothesis for sodium channels. J. Neurophysiol. 71, 2562–2565.

    CAS  PubMed  Google Scholar 

  8. 8.

    Butera, R. J., Jr., Rinzel, J., Smith, J. C. (1999) Models of respiratory rhythm generation in the pre- Botzinger complex. I. Bursting pacemaker neurons. J. Neurophysiol. 82, 382–397.

    PubMed  Google Scholar 

  9. 9.

    Caffrey, J. M., Eng, D. L., Black, J. A., Waxman, S. G., Kocsis, J. D. (1992) Three types of sodium channels in adult rat dorsal root ganglion neurons. Brain Res. 592, 283–297.

    CAS  PubMed  Google Scholar 

  10. 10.

    Chandler, W. K., Meves, H. (1970) Evidence for two types of sodium conductance in axons perfused with sodium fluoride solution. J. Physiol. 211, 653–678.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Chen, N., Lucero, M. T. (1999) Transient and persistent tetrodotoxin-sensitive sodium currents in squid olfactory receptor neurons. J. Comp. Physiol. . 184, 63–72.

    Google Scholar 

  12. 12.

    Clay, J. R. (2003) On the persistent sodium current in squid giant axons. J. Neurophysiol. 89, 640–644.

    CAS  PubMed  Google Scholar 

  13. 13.

    Colmers, W. F., Lewis, D. V., Wilson, W. A. (1982) Cs+ loading reveals Na+-dependent persistent inward current and negative slope resistance region in Aplysia giant neurons. J. Neurophysiol. 48, 1191–1200.

    CAS  PubMed  Google Scholar 

  14. 14.

    Correa, A. M., Bezanilla, F. (1994) Gating of the squid sodium channel at positive potentials: II. Single channels reveal two open states. Biophys. J. 66, 1864–1878.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Cox, J. J., Reimann, F., Nicholas, A. K., Thornton, G., Roberts, E., Springell, K., Karbani, G., Jafri, H., Mannan, J., Raashid, Y., Al-Gazali, L., Hamamy, H., Valente, E. M., Gorman, S., Williams, R., McHale, D. P., Wood, J. N., Gribble, F. M. Woods, C. G. (2006) An SCN9A channelopathy causes congenital inability to experience pain. Natur. 444, 894–898.

    CAS  Google Scholar 

  16. 16.

    Crill, W. E. (1996) Persistent sodium current in mammalian central neurons. Annu. Rev. Physiol. 58, 349–362.

    CAS  PubMed  Google Scholar 

  17. 17.

    Cummins, T. R., Howe, J. R., Waxman, S. G. (1998) Slow closed-state inactivation: a novel mechanism underlying ramp currents in cells expressing the hNE/PN1 sodium channel. J. Neurosci. 18, 9607–9619.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Davis, R. E., Stuart, A. E. (1988) A persistent, TTX-sensitive sodium current in an invertebrate neuron with neurosecretory ultrastructure. J. Neurosci. 8, 3978–3991.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Defaix, A., Lapied, B. (2005) Role of a novel maintained low-voltage-activated inward current permeable to sodium and calcium in pacemaking of insect neurosecretory neurons. Invert. Neurosci. 5, 135–146.

    CAS  PubMed  Google Scholar 

  20. 20.

    Dib-Hajj, S., Black, J. A., Cummins, T. R., Waxman, S. G. (2002) NaN/Nav1.9: a sodium channel with unique properties. Trends Neurosci. 25, 253–259.

    CAS  PubMed  Google Scholar 

  21. 21.

    Elinder, F., Arhem, P. (1997) Tail currents in the myelinated axon of Xenopus laevis suggest a twoopen- state Na channel. Biophys. J. 73, 179–185.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Fleidervish, I. A., Gutnick, M. J. (1996) Kinetics of slow inactivation of persistent sodium current in layer V neurons of mouse neocortical slices. J. Neurophysiol. 76, 2125–2130.

    CAS  PubMed  Google Scholar 

  23. 23.

    French, C. R., Sah, P., Buckett, K. J., Gage, P. W. (1990) A voltage-dependent persistent sodium current in mammalian hippocampal neurons. J. Gen. Physiol. 95, 1139–1157.

    CAS  PubMed  Google Scholar 

  24. 24.

    Gilly, W. F., Armstrong, C. M. (1984) Threshold channels–a novel type of sodium channel in squid giant axon. Natur. 309, 448–450.

    CAS  Google Scholar 

  25. 25.

    Hammarström, A. K. M., Gage, P. W. (1999) Nitric oxide increases persistent sodium current in rat hippocampal neurons. J. Physiolog. 520, 451–461.

    Google Scholar 

  26. 26.

    Herzog, R. I., Cummins, T. R., Waxman, S. G. (2001) Persistent TTX-resistant Na+ current affects resting potential and response to depolarization in simulated spinal sensory neurons. J. Neurophysiol. 86, 1351–1364.

    CAS  PubMed  Google Scholar 

  27. 27.

    Hutcheon, B., Miura, R. M., Puil, E. (1996) Subthreshold membrane resonance in neocortical neurons. J. Neurophysiol. 76, 683–697.

    CAS  PubMed  Google Scholar 

  28. 28.

    Kallen, R. G., Sheng, Z. H., Yang, J., Chen, L. Q., Rogart, R. B., Barchi, R. L. (1990) Primary structure and expression of a sodium channel characteristic of denervated and immature rat skeletal muscle. Neuro. 4, 233–242.

    CAS  Google Scholar 

  29. 29.

    Kay, A. R., Sugimori, M., Llinas, R. (1998) Kinetic and stochastic properties of a persistent sodium current in mature guinea pig cerebellar Purkinje cells. J. Neurophysiol. 80, 1167–1179.

    CAS  PubMed  Google Scholar 

  30. 30.

    Kirsch, G. E., Brown, A. M. (1989) Kinetic properties of single sodium channels in rat heart and rat brain. J. Gen. Physiol. 93, 85–99.

    CAS  PubMed  Google Scholar 

  31. 31.

    Kiss, T. (2003) Evidence for a persistent Na-conductance in identified command neurones of the snail, Helix pomatia. Brain Res. 989, 16–25.

    CAS  PubMed  Google Scholar 

  32. 32.

    Kiss, T., Pirger, Z., Kemenes, G. (2008) Food aversive conditioning increases persistent current carried in withdrawal interneurons. Learn. Memory (submitted).

    Google Scholar 

  33. 33.

    Llinas, R., Sugimori, M. (1980) Electrophysiological properties of in vitro Purkinje cell somata in mammalian cerebellar slices. J. Physiol. 305, 171–195.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Magistretti, J., Alonso, A. (1999) Biophysical properties and slow voltage-dependent inactivation of a sustained sodium current in entorhinal cortex layer-II principal neurons: a whole-cell and singlechannel study. J. Gen. Physiol. 114, 491–509.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Magistretti, J., Ragsdale, D. S., Alonso, A. (1999) High conductance sustained single-channel activity responsible for the low-threshold persistent Na(+) current in entorhinal cortex neurons. J. Neurosci. 19, 7334–7341.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Maurice, N., Tkatch, T., Meisner, M., Sprunger, L. K., Surmeier, D. J. (2001) D1/D5 dopamine receptor activation differentially modulates rapidly inactivating and presistent sodium currents in prefrontal cortex pyramid. J. Neurosci. 21, 2268–2277.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Mittmann, T., Alzheimer, C. (1998) Muscarinic inhibition of persistent Na+ current in rat neocortical pyramidal neurons. J. Neurophysiol. 79, 1579–1582.

    CAS  PubMed  Google Scholar 

  38. 38.

    Nagy, K., Kiss, T., Hof, D. (1983) Single Na channels in mouse neuroblastoma cell membrane. Indications for two open states. Pflugers Arch. 399, 302–308.

    CAS  PubMed  Google Scholar 

  39. 39.

    Nikitin, E. S., Kiss, T., Staras, K., O’Shea, M., Benjamin, P. R., Kemenes, G. (2006) Persistent sodium current is a target for cAMP-induced neuronal plasticity in a state-setting modulatory interneuron. J. Neurophysiol. 95, 453–463.

    CAS  PubMed  Google Scholar 

  40. 40.

    Nikitin, E. S., Vavoulis, D. V., Feng, J., O’Shea, M., Benjamin, P. R., Kemenes, G. (2008) Persistent sodium current is a non-synaptic substrate for memory (submitted).

    Google Scholar 

  41. 41.

    Ochs, G., Bromm, B., Schwarz, J. R. (1981) A three-state model for inactivation of sodium permeability. Biochim. Biophys. Act. 645, 243–252.

    CAS  Google Scholar 

  42. 42.

    Ogata, N., Ohishi, Y. (2002) Molecular diversity of structure and function of the voltage-gated Na+ channels. Jpn. J. Pharmacol. 88, 365–377.

    CAS  PubMed  Google Scholar 

  43. 43.

    Opdyke, C. A., Calabrese, R. L. (1994) A persistent sodium current contributes to oscillatory activity in heart interneurons of the medicinal leech. J. Comp. Physiol. [A]. 175, 781–789.

    CAS  Google Scholar 

  44. 44.

    Patlak, J. B., Ortiz, M. (1985) Slow currents through single sodium channels of the adult rat heart. J. Gen. Physiol. 86, 89–104.

    CAS  PubMed  Google Scholar 

  45. 45.

    Patlak, J. B., Ortiz, M. (1986) Two modes of gating during late Na+ channel currents in frog sartorius muscle. J. Gen. Physiol. 87, 305–326.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Plummer, N. W., Meisler, M. H. (1999) Evolution and diversity of mammalian sodium channel genes. Genomic. 57, 323–331.

    CAS  Google Scholar 

  47. 47.

    Raman, I. M., Bean, B. P. (1997) Resurgent sodium current and action potential formation in dissociated cerebellar Purkinje neurons. J. Neurosci. 17, 4517–4526.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Raman, I. M., Bean, B. P. (1999) Ionic currents underlying spontaneous action potentials in isolated cerebellar Purkinje neurons. J. Neurosci. 19, 1663–1674.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Raman, I. M., Bean, B. P. (2001) Inactivation and recovery of sodium currents in cerebellar Purkinje neurons: evidence for two mechanisms. Biophys. J. 80, 729–737.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Renganathan, M., Dib-Hajj, S., Waxman, S. G. (2002) Na(v)1.5 underlies the ‘third TTX-R sodium current’ in rat small DRG neurons. Brain Res. Mol. Brain Res. 106, 70–82.

    CAS  PubMed  Google Scholar 

  51. 51.

    Roy, M. L., Narahashi, T. (1992) Differential properties of tetradotoxin-sensitive and tetrodotoxinresistant sodium channels in rat dorsal root ganglion neurons. J. Neurosci. 12, 2104–2111.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Rudy, B. (1978) Slow inactivation of the sodium conductance in squid giant axons. Pronase resistance. J. Physiol. 283, 1–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Saint, D. A., Ju, Y. K., Gage, P. W. (1992) A persistent sodium current in rat ventricular myocytes. J. Physiol. 453, 219–231.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Salgado, V. L., Yeh, J. Z., Narahashi, T. (1985) Voltage-dependent removal of sodium inactivation by N-bromoacetamide and pronase. Biophys. J. 47, 567–571.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Stimers, J. R., Byerly, L. (1982) Slowing of sodium current inactivation by ruthenium red in snail neurons. J. Gen. Physiol. 80, 485–497.

    CAS  PubMed  Google Scholar 

  56. 56.

    Taddese, A., Bean, B. P. (2002) Subthreshold sodium current from rapidly inactivating sodium channels drives spontaneous firing of tuberomammillary neurons. Neuro. 33, 587–600.

    CAS  Google Scholar 

  57. 57.

    The, Y. K., Fernandes, J., Popa, M. O., Alekov, A. K., Timmer, J., Lerche, H. (2006) Modeling of single noninactivating Na+ channels: evidence for two open and several fast inactivated states. Biophys. J. 90, 3511–3522.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Trimmer, J. S., Cooperman, S. S., Tomiko, S. A., Zhou, J. Y., Crean, S. M., Boyle, M. B., Kallen, R. G., Sheng, Z. H., Barchi, R. L., Sigworth, F. J. et al. (1989) Primary structure and functional expression of a mammalian skeletal muscle sodium channel. Neuro. 3, 33–49.

    CAS  Google Scholar 

  59. 59.

    Turrigiano, G., LeMasson, G., Marder, E. (1995) Selective regulation of current densities underlies spontaneous changes in the activity of cultured neurons. J. Neurosci. 15, 3640–3652.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Ulbricht, W. (2005) Sodium channel inactivation: molecular determinants and modulation. Physiol. Rev. 85, 1271–1301.

    CAS  PubMed  Google Scholar 

  61. 61.

    Waxman, S. G., Hains, B. C. (2006) Fire and phantoms after spinal cord injury: Na+ channels and central pain. Trends Neurosci. 29, 207–215.

    CAS  PubMed  Google Scholar 

Download references

Author information



Corresponding author

Correspondence to T. Kiss.

Rights and permissions

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Reprints and Permissions

About this article

Cite this article

Kiss, T. Persistent Na-Channels: Origin and Function. BIOLOGIA FUTURA 59, 1–12 (2008).

Download citation


  • Persistent Na-channel
  • invertebrates
  • vertebrates
  • kinetic models
  • function