Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Annexin II light chain regulates sensory neuron-specific sodium channel expression


The tetrodotoxin-resistant sodium channel NaV1.8/SNS is expressed exclusively in sensory neurons and appears to have an important role in pain pathways1,2. Unlike other sodium channels, NaV1.8 is poorly expressed in cell lines even in the presence of accessory β-subunits3. Here we identify annexin II light chain4,5 (p11) as a regulatory factor that facilitates the expression of NaV1.8. p11 binds directly to the amino terminus of NaV1.8 and promotes the translocation of NaV1.8 to the plasma membrane, producing functional channels. The endogenous NaV1.8 current in sensory neurons is inhibited by antisense downregulation of p11 expression. Because direct association with p11 is required for functional expression of NaV1.8, disrupting this interaction may be a useful new approach to downregulating NaV1.8 and effecting analgesia6.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1: p11 mRNA is expressed in DRG neurons and is upregulated by NGF.
Figure 2: p11 regulates trafficking of NaV1.8 from cytosol to plasma membrane.
Figure 3: p11 is required for expression of TTX-resistant inward currents in CHO-SNS22 and DRG neurons.

Similar content being viewed by others


  1. Akopian, A. N., Sivilotti, L. & Wood, J. N. A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. Nature 379, 257–262 (1996)

    Article  ADS  CAS  Google Scholar 

  2. Akopian, A. N. et al. The tetrodotoxin-resistant sodium channel SNS plays a specialized role in pain pathways. Nature Neurosci. 2, 541–548 (1999)

    Article  CAS  Google Scholar 

  3. Isom, L. L. Sodium channel beta subunits: anything but auxiliary. Neuroscientist 7, 42–54 (2000)

    Article  Google Scholar 

  4. Waisman, D. M. Annexin II tetramer: structure and function. Mol. Cell. Biochem. 149/150, 301–322 (1995)

    Article  Google Scholar 

  5. Osborn, M., Johnsson, N., Wehland, J. & Weber, K. The submembranous location of p11 and its interaction with the p36 substrate of pp60 src kinase in situ. Exp. Cell. Res. 175, 81–96 (1988)

    Article  CAS  Google Scholar 

  6. Waxman, S. G. et al. Sodium channels, excitability of primary sensory neurons, and the molecular basis of pain. Muscle Nerve 22, 1177–1187 (1999)

    Article  CAS  Google Scholar 

  7. Goldin, A. L. et al. Nomenclature of voltage-gated sodium channels. Neuron 28, 365–368 (2000)

    Article  CAS  Google Scholar 

  8. Isom, L. L. et al. Functional co-expression of the beta 1 and type IIA alpha subunits of sodium channels in a mammalian cell line. J. Biol. Chem. 270, 3306–3312 (1995)

    Article  CAS  Google Scholar 

  9. England, S., Okuse, K., Ogata, N. & Wood, J. N. Heterologous expression of the sensory neurone-specific sodium channel (SNS) α-subunit in rat sympathetic neurones. J. Physiol. 511, 124P (1998)

    Google Scholar 

  10. Fitzgerald, E. M. et al. cAMP-dependent phosphorylation of the tetrodotoxin-resistant voltage-dependent sodium channel SNS. J. Physiol. 516, 433–446 (1999)

    Article  CAS  Google Scholar 

  11. Kong, H. et al. An evolutionarily conserved transmembrane protein that is a novel downstream target of neurotrophin and ephrin receptors. J. Neurosci. 21, 176–185 (2001)

    Article  CAS  Google Scholar 

  12. Liu, C. J., Dib-Hajj, S. D. & Waxman, S. G. Fibroblast growth factor homologous factor 1B binds to the C terminus of the tetrodotoxin-resistant sodium channel rNav1.9a (NaN). J. Biol. Chem. 276, 18925–18933 (2001)

    Article  CAS  Google Scholar 

  13. Lewin, G. R., Rueff, A. & Mendell, L. M. Peripheral and central mechanisms of NGF-induced hyperalgesia. Eur. J. Neurosci. 6, 1903–1912 (1994)

    Article  CAS  Google Scholar 

  14. Black, J. A. et al. NGF has opposing effects on Na+ channel III and SNS gene expression in spinal sensory neurons. Neuroreport 8, 2331–2335 (1997)

    Article  CAS  Google Scholar 

  15. Fang, X. et al. Sensory and electrophysiological properties of DRG neurones with SNS-like immunoreactivity (SNS-LI) in rats. Soc. Neurosci. Abstr. no. 819.5 (2001).

  16. Pollard, H. B. & Rojas, E. Calcium activated synexin forms higly selective voltage-gated calcium channels in phosphatidylserine bilayer membranes. Proc. Natl Acad. Sci. USA 85, 2974–2978 (1988)

    Article  ADS  CAS  Google Scholar 

  17. Nilius, B. et al. Annexin II modulates volume activated chloride channels in vascular endothelial cells. J. Biol. Chem. 271, 30631–30636 (1996)

    Article  CAS  Google Scholar 

  18. Baker, M. D. & Wood, J. N. Involvement of Na+ channels in pain pathways. Trends Pharmacol. Sci. 22, 27–31 (2001)

    Article  CAS  Google Scholar 

  19. Pawliczak, R. et al. p11 expression in human bronchial epithelial cells is increased by nitric oxide in a cGMP-dependent pathway involving protein kinase G activation. J. Biol. Chem. 276, 44613–44620 (2001)

    Article  CAS  Google Scholar 

  20. Aley, K. O., McCarter, G. & Levine, J. D. Nitric oxide signalling in pain and nociceptor sensitization in the rat. J. Neurosci. 18, 7008–7014 (1998)

    Article  CAS  Google Scholar 

  21. Yao, X. L. et al. Dexamethasone alters arachidonate release from human epithelial cells by induction of p11 protein synthesis and inhibition of phospholipase A2 activity. J. Biol. Chem. 274, 17202–17208 (1999)

    Article  CAS  Google Scholar 

  22. Garber, S. S., Hoshi, T. & Aldrich, R. W. Regulation of ionic currents in pheochromocytoma cells by nerve growth factor and dexamethasone. J. Neurosci. 9, 3976–3987 (1989)

    Article  CAS  Google Scholar 

  23. Akiba, S. et al. Transforming growth factor-α stimulates prostaglandin generation through cytosolic phospholipase A2 under the control of p11 in rat gastric epithelial cells. Br. J. Pharmacol. 131, 1004–1010 (2000)

    Article  CAS  Google Scholar 

  24. Masiakowski, P. & Shooter, E. M. Nerve growth factor induces the genes for two proteins related to a family of calcium-binding proteins in PC12 cells. Proc. Natl Acad. Sci. USA 85, 1277–1281 (1988)

    Article  ADS  CAS  Google Scholar 

  25. Fjell, J. et al. In vivo NGF deprivation reduces SNS expression and TTX-R sodium currents in IB4-negative DRG neurons. J. Neurophysiol. 81, 803–810 (1999)

    Article  CAS  Google Scholar 

  26. Okuse, K. et al. Regulation of expression of the sensory neuron-specific sodium channel SNS in inflammatory and neuropathic pain. Mol. Cell. Neurosci. 10, 196–207 (1997)

    Article  CAS  Google Scholar 

  27. Gold, M. S. Tetrodotoxin-resistant Na+ currents and inflammatory hyperalgesia. Proc. Natl Acad. Sci. USA 96, 7645–7649 (1999)

    Article  ADS  CAS  Google Scholar 

Download references


We thank the MRC, the Wellcome Trust and the NIH (grants supporting M.C. and H.K.) for their generous support. We thank Stephen E. Moss and A. Schmidt for helpful advice.

Author information

Authors and Affiliations


Corresponding author

Correspondence to John N. Wood.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Okuse, K., Malik-Hall, M., Baker, M. et al. Annexin II light chain regulates sensory neuron-specific sodium channel expression. Nature 417, 653–656 (2002).

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing