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.

A calcium sensor in the sodium channel modulates cardiac excitability


Sodium channels are principal molecular determinants responsible for myocardial conduction and maintenance of the cardiac rhythm. Calcium ions (Ca2+) have a fundamental role in the coupling of cardiac myocyte excitation and contraction, yet mechanisms whereby intracellular Ca2+ may directly modulate Na channel function have yet to be identified. Here we show that calmodulin (CaM), a ubiquitous Ca2+-sensing protein, binds to the carboxy-terminal ‘IQ’ domain1 of the human cardiac Na channel (hH1) in a Ca2+-dependent manner. This binding interaction significantly enhances slow inactivation—a channel-gating process linked to life-threatening idiopathic ventricular arrhythmias2,3. Mutations targeted to the IQ domain disrupted CaM binding and eliminated Ca2+/CaM-dependent slow inactivation, whereas the gating effects of Ca2+/CaM were restored by intracellular application of a peptide modelled after the IQ domain. A naturally occurring mutation (A1924T) in the IQ domain altered hH1 function in a manner characteristic of the Brugada arrhythmia syndrome4,5, but at the same time inhibited slow inactivation induced by Ca2+/CaM, yielding a clinically benign (arrhythmia free) phenotype.

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

Access options

Rent or buy this article

Prices vary by article type



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

Figure 1: Inactivation gating of hH1 is sensitive to Ca2+ and CaM.
Figure 2: Conditional changes in slow inactivation in wild-type and mutant hH1 channels.
Figure 3: A mutation in the IQ domain alters Ca2+/CaM sensitivity.
Figure 4: Inactivation gating properties of the A1924T mutation in the IQ domain.


  1. Zuhlke, R. D. & Reuter, H. Ca2+-sensitive inactivation of L-type Ca2+ channels depends on multiple cytoplasmic amino acid sequences of the alpha1C subunit. Proc. Natl Acad. Sci. USA 95, 3287–3294 (1998).

    Article  ADS  CAS  Google Scholar 

  2. Veldkamp, M. W. et al. Two distinct congenital arrhythmias evoked by a multidysfunctional Na+ channel. Circ. Res. 86, E91–E97 (2000).

    Article  CAS  Google Scholar 

  3. Wang, D. W., Makita, N., Kitabatake, A., Balser, J. R. & George, A. L. Enhanced sodium channel intermediate inactivation in Brugada syndrome. Circ. Res. 87, E37–E43 (2000).

    Article  CAS  Google Scholar 

  4. Chen, Q. et al. Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. Nature 392, 293–296 (1998).

    Article  ADS  CAS  Google Scholar 

  5. Dumaine, R. et al. Ionic mechanisms responsible for the electrocardiographic phenotype of the Brugada syndrome are temperature dependent. Circ. Res. 85, 803–809 (1999).

    Article  CAS  Google Scholar 

  6. Babu, Y. S. et al. Three-dimensional structure of calmodulin. Nature 315, 37–40 (1985).

    Article  ADS  CAS  Google Scholar 

  7. Lee, A. et al. Ca2+/calmodulin binds to and modulates P/Q-type calcium channels. Nature 399, 155–159 (1999).

    Article  ADS  CAS  Google Scholar 

  8. DeMaria, C. D., Soong, T. W., Alseikhan, B. A., Alvania, R. S. & Yue, D. T. Calmodulin bifurcates the local Ca2+ signal that modulates P/Q-type Ca2+ channels. Nature 411, 484–489 (2001).

    Article  ADS  CAS  Google Scholar 

  9. Mori, M. et al. Novel interaction of the voltage-dependent sodium channel (VDSC) with calmodulin: does VDSC acquire calmodulin-mediated Ca2+-sensitivity? Biochemistry 39, 1316–1323 (2000).

    Article  CAS  Google Scholar 

  10. Payne, M. E. et al. Calcium/calmodulin-dependent protein kinase II. Characterization of distinct calmodulin binding and inhibitory domains. J. Biol. Chem. 263, 7190–7195 (1988).

    CAS  Google Scholar 

  11. Hanley, R. M. et al. Functional analysis of a complementary DNA for the 50-kilodalton subunit of calmodulin kinase II. Science 237, 293–297 (1987).

    Article  ADS  CAS  Google Scholar 

  12. Rudy, B. Slow inactivation of the sodium conductance in squid giant axons. Pronase resistance. J. Physiol. (Lond.) 238, 1–21 (1978).

    Article  Google Scholar 

  13. Richmond, J. E., Featherstone, D. E., Hartmann, H. A. & Ruben, P. C. Slow inactivation in human cardiac sodium channels. Biophys. J. 74, 2945–2952 (1998).

    Article  ADS  CAS  Google Scholar 

  14. Todt, H., Dudley, S. C. Jr, Kyle, J. W., French, R. J. & Fozzard, H. A. Ultra-slow inactivation in mu1 Na+ channels is produced by a structural rearrangement of the outer vestibule. Biophys. J. 76, 1335–1345 (1999).

    Article  CAS  Google Scholar 

  15. Keen, J. E. et al. Domains responsible for constitutive and Ca(2+)-dependent interactions between calmodulin and small conductance Ca(2+)-activated potassium channels. J. Neurosci. 19, 8830–8838 (1999).

    Article  CAS  Google Scholar 

  16. Xia, X. M. et al. Mechanism of calcium gating in small-conductance calcium-activated potassium channels. Nature 395, 503–507 (1998).

    Article  ADS  CAS  Google Scholar 

  17. Rhoads, A. R. & Friedberg, F. Sequence motifs for calmodulin recognition. FASEB J. 11, 331–340 (1997).

    Article  CAS  Google Scholar 

  18. Maune, J. F., Klee, C. B. & Beckingham, K. Ca2+ binding and conformational change in two series of point mutations to the individual Ca(2+)-binding sites of calmodulin. J. Biol. Chem. 267, 5286–5295 (1992).

    CAS  Google Scholar 

  19. Brugada, P. & Brugada, J. Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. A multicenter report. J. Am. Coll. Cardiol. 20, 1391–1396 (1992).

    Article  CAS  Google Scholar 

  20. Tiso, N. et al. Identification of mutations in the cardiac ryanodine receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2). Hum. Mol. Genet. 10, 189–194 (2001).

    Article  CAS  Google Scholar 

  21. Rook, M. B. et al. Human SCN5A gene mutations alter cardiac sodium channel kinetics and are associated with the Brugada syndrome. Cardiovasc. Res. 44, 507–517 (1999).

    Article  CAS  Google Scholar 

  22. Wilde, A. A. M. & Duren, D. Sudden cardiac death, RBBB, and right precordial ST-segment elevation. Circulation 99, 722–723 (1999).

    Article  CAS  Google Scholar 

  23. Balser, J. R. Sodium ‘channelopathies’ and sudden death: must you be so sensitive? Circ. Res. 85, 872–874 (1999).

    Article  CAS  Google Scholar 

  24. Clusin, W. T., Buchbinder, M. & Harrison, D. C. Calcium overload, ‘injury’ current, and early ischaemic cardiac arrhythmias—a direct connection. Lancet 1, 272–274 (1983).

    Article  CAS  Google Scholar 

  25. Di Diego, J. M. & Antzelevitch, C. High [Ca2+]o-induced electrical heterogeneity and extrasystolic activity in isolated canine ventricular epicardium. Phase 2 reentry. Circulation 89, 1839–1850 (1994).

    Article  CAS  Google Scholar 

  26. Aimond, F., Alvarez, J. L., Rauzier, J. M., Lorente, P. & Vassort, G. Ionic basis of ventricular arrhythmias in remodeled rat heart during long-term myocardial infarction. Cardiovasc. Res. 42, 402–415 (1999).

    Article  CAS  Google Scholar 

  27. Tan, H. L. et al. A sodium channel mutation causes isolated cardiac conduction disease. Nature 409, 1043–1047 (2001).

    Article  ADS  CAS  Google Scholar 

  28. Bers, D. M., Patton, C. W. & Nuccitelli, R. A practical guide to the preparation of Ca2+ buffers. Methods Cell Biol. 40, 3–29 (1994).

    Article  CAS  Google Scholar 

  29. Braun, A. P. & Schulman, H. A non-selective cation current activated via the multifunctional Ca(2+)-calmodulin-dependent protein kinase in human epithelial cells. J. Physiol. (Lond.) 488, 37–55 (1995).

    Article  CAS  Google Scholar 

  30. James, P., Halladay, J. & Craig, E. A. Genomic libraries and a host strain designed for highly efficient two-hybrid selection in yeast. Genetics 144, 1425–1436 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references


We acknowledge C. R. Bezzina for genetic analysis of A1924T, C. A. Conrath for subcloning A1924T, and A. George for critique. H.L.T. was supported by a fellowship from the Royal Netherlands Academy of Arts and Sciences. Additional financial support was provided by the Interuniversity Cardiology Institute Netherlands project 27 (H.L.T. and A.A.M.W.), the Dutch Heart Foundation NHS (A.A.M.W.), and National Institutes of Health grants (M.E.A. and J.R.B.).

Author information

Authors and Affiliations


Corresponding author

Correspondence to Jeffrey R. Balser.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tan, H., Kupershmidt, S., Zhang, R. et al. A calcium sensor in the sodium channel modulates cardiac excitability. Nature 415, 442–447 (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