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Pflügers Archiv - European Journal of Physiology

, Volume 455, Issue 5, pp 929–938 | Cite as

A comparison of the effects of veratridine on tetrodotoxin-sensitive and tetrodotoxin-resistant sodium channels in isolated rat dorsal root ganglion neurons

  • K. J. Farrag
  • A. Bhattacharjee
  • R. J. DochertyEmail author
Ion Channels

Abstract

The effects of veratridine have been compared on tetrodotoxin-sensitive (TTXS) and tetrodotoxin-resistant (TTXR) voltage-gated sodium channels (VGSC) in rat dorsal root ganglion neurons. Veratridine caused a dose-dependent decrease in the peak amplitude of both TTXR and TTXS VGSC currents. When exposed to 25 μM veratridine, TTXS currents but not TTXR currents developed a clear persistent component. The deactivation of both TTXS and TTXR currents was slowed, as evidenced by the appearance of slowly decaying tail currents in voltage clamp records, but the slowing of deactivation was nearly 100 times greater for TTXS than for TTXR currents. Properties of the veratridine-modified VGSCs, derived from an analysis of the slow tail currents, were similar for both TTXS and TTXR in that the V50 for activation and the reversal potential were shifted to more negative potentials than control currents and by a similar amount for each. The relatively fast decay of veratridine-modified TTXR tail currents reflects a faster dissociation of veratridine from TTXR than from TTXS VGSCs. This difference probably underlies the lack of effect of veratridine on TTXR VGSCs in cells that are not voltage-clamped and undermines its value as a chemical activator of putative NaV1.8 TTXR channels.

Keywords

Sodium channel Dorsal root ganglion Veratridine Tetrodotoxin Sensory neuron Pain 

Notes

Acknowledgements

We thank the Trustees of Guy’s and St. Thomas’ Charitable Foundation (grant ref. 970595) and The Migraine Trust for their financial support.

References

  1. 1.
    Barnes S, Hille B (1988) Veratridine modifies open sodium channels. J Gen Physiol 91:421–443PubMedCrossRefGoogle Scholar
  2. 2.
    Benjamin ER, Pruthi F, Olanrewaju S, Ilyin VI, Crumley G, Kutlina E, Valenzano KJ, Woodward RM (2006) State-dependent compound inhibition of NaV1.2 sodium channels using the FLIPR Vm dye: on-target effects of diverse pharmacological agents. J Biomol Screen 11:29–39PubMedCrossRefGoogle Scholar
  3. 3.
    Campos FV, Moreira TH, Beirao PSL, Cruz JS (2004) Veratridine modifies the TTX-resistant Na+ channels in rat vagal afferent neurons. Toxicon 43:401–406PubMedCrossRefGoogle Scholar
  4. 4.
    Catterall WA (1980) Neurotoxins that act on voltage-sensitive sodium channels in excitable membranes. Ann Rev Pharmacol Toxicol 20:15–43CrossRefGoogle Scholar
  5. 5.
    Cestele S, Catterall WA (2000) Molecular mechanisms of neurotoxin action on voltage-gated sodium channels. Biochimie 82:883–892PubMedCrossRefGoogle Scholar
  6. 6.
    Denac H, Mevissen M, Scholtysik G (2000) Structure, function and pharmacology of voltage-gated sodium channels. Naunyn-Schmiedeberg’s Arch Pharmacol 362:453–479CrossRefGoogle Scholar
  7. 7.
    Docherty RJ, Farrag KJ (2006) The effect of dibutyryl cAMP on tetrodotoxin-sensitive and -resistant voltage-gated sodium currents in rat dorsal root ganglion neurons and the consequences for their sensitivity to lidocaine. Neuropharmacology 51:1047–1057PubMedCrossRefGoogle Scholar
  8. 8.
    Fitzgerald EM, Okuse K, Wood JN, Dolphin AC, Moss SJ (1999) cAMP-dependent phosphorylation of the tetrodotoxin-resistant voltage-gated sodium channel SNS. J Physiol 516:433–446PubMedCrossRefGoogle Scholar
  9. 9.
    Ghatpande AS, Sikdar SK (1997) Competition for binding between veratridine and KIFMK: an open channel blocking peptide of the RIIA sodium channel. J Membrane Biol 160:177–182CrossRefGoogle Scholar
  10. 10.
    Ghatpande AS, Sikdar SK (1999) Voltage-dependent gating of veratridine-modified RIIA Na+ channel α subunit expressed heterologously in CHO cells. Pflugers Arch Eur J Physiol 438:378–383CrossRefGoogle Scholar
  11. 11.
    Hille B (1968) Pharmacological modifications of the sodium channels of frog nerve. J Gen Physiol 51:199–219PubMedCrossRefGoogle Scholar
  12. 12.
    Hille B (2001) In Ionic channels of excitable membranes, 3rd edn. Sinauer, Sunderland, MA, pp 641–645Google Scholar
  13. 13.
    Jarvis MF, Honore P, Shieh CC, Chapman M, Joshi S, Zhang XF, Kort M, Carroll W, Marron B, Atkinson R, Thomas J, Liu D, Krambis M, Liu Y, McGaraughty S, Chu K, Roeloffs R, Zhong C, Mikusa JP, Hernandez G, Gauvin D, Wade C, Zhu C, Pai M, Scanio M, Shi L, Drizin I, Gregg R, Matulenko M, Hakeem A, Gross M, Johnson M, Marsh K, Wagoner PK, Sullivan JP, Faltynek CR, Krafte DS (2007) A-803467, a potent and selective Nav1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat. Proc Natl Acad Sci USA 104:8520–8525PubMedCrossRefGoogle Scholar
  14. 14.
    Leibowitz MD, Sutro JB, Hille B (1986) Voltage-dependent gating of veratridine-modified Na channels. J Gen Physiol 87:25–46PubMedCrossRefGoogle Scholar
  15. 15.
    Liu CJ, Priest BT, Bugianesi RM, Dulski PM, Felix JP, Dick IE, Brochu RM, Knaus H-G, Middleton RE, Kaczorowski GJ, Slaughter RS, Garcia ML, Kohler MG (2006) A high-capacity membrane potential FRET-based assay for NaV1.8 channels. Assay Drug Develop Technol 4:37–48CrossRefGoogle Scholar
  16. 16.
    Sutro JB (1986) Kinetics of veratridine action on Na channels of skeletal muscle. J Gen Physiol 87:1–24PubMedCrossRefGoogle Scholar
  17. 17.
    Tikhonov DB, Zhorov BS (2005) Sodium channel activators: model of binding inside the pore and a possible mechanism of action. FEBS Lett 579:4207–4212PubMedCrossRefGoogle Scholar
  18. 18.
    Ulbricht W (1998) Effects of veratridine on sodium channels and fluxes. Rev Physiol Biochem Pharmacol 133:1–54PubMedGoogle Scholar
  19. 19.
    Vickery RG, Amagasu SM, Chang R, Mai N, Kauman E, Martin J, Hembrador J, O, Keefe MD, Gee C, Marquess D, Smith JA (2004) Comparison of the pharmacological properties of rat Na(V)1.8 with Rat Na(V) 1.2a and human Na(V)1.5 voltage-gated sodium channel subtypes using a membrane potential sensitive dye and FLIPR. Receptors Channels 10:11–23PubMedCrossRefGoogle Scholar
  20. 20.
    Wang S-Y, Wang GK (2003) Voltage-gated sodium channels as primary targets of diverse lipid-soluble neurotoxins. Cell Signal 15:151–159PubMedCrossRefGoogle Scholar
  21. 21.
    Weiser (2004) A novel toxicity-based assay for the identification of modulators of voltage-gated Na+ channels. J Neurosci Methods 137:79–85PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • K. J. Farrag
    • 1
  • A. Bhattacharjee
    • 1
  • R. J. Docherty
    • 2
    Email author
  1. 1.Wolfson Centre for Age-related Diseases, School of Biomedical and Health SciencesKing’s College LondonLondonUK
  2. 2.Wolfson Centre for Age-Related Diseases, Guy’s Campus, London BridgeKing’s College LondonLondonUK

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