Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2004 Sep 22;24(38):8232-6.
doi: 10.1523/JNEUROSCI.2695-04.2004.

Electrophysiological properties of mutant Nav1.7 sodium channels in a painful inherited neuropathy

Theodore R Cummins  1 , Sulayman D Dib-Hajj, Stephen G Waxman
Affiliations

Electrophysiological properties of mutant Nav1.7 sodium channels in a painful inherited neuropathy

Theodore R Cummins et al. J Neurosci. .

Abstract

Although the physiological basis of erythermalgia, an autosomal dominant painful neuropathy characterized by redness of the skin and intermittent burning sensation of extremities, is not known, two mutations of Na(v)1.7, a sodium channel that produces a tetrodotoxin-sensitive, fast-inactivating current that is preferentially expressed in dorsal root ganglia (DRG) and sympathetic ganglia neurons, have recently been identified in patients with primary erythermalgia. Na(v)1.7 is preferentially expressed in small-diameter DRG neurons, most of which are nociceptors, and is characterized by slow recovery from inactivation and by slow closed-state inactivation that results in relatively large responses to small, subthreshold depolarizations. Here we show that these mutations in Na(v)1.7 produce a hyperpolarizing shift in activation and slow deactivation. We also show that these mutations cause an increase in amplitude of the current produced by Na(v)1.7 in response to slow, small depolarizations. These observations provide the first demonstration of altered sodium channel function associated with an inherited painful neuropathy and suggest that these physiological changes, which confer hyperexcitability on peripheral sensory and sympathetic neurons, contribute to symptom production in hereditary erythermalgia.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
The I848T and L858H mutations of hNav1.7 alter activation and deactivation. A, Current traces recorded from representative HEK293 cells expressing either wild-type hNav1.7 or mutant channels, I848T or L858H. Cells were held at -100 mV, and currents were elicited with 50 msec test pulses to potentials ranging from -80 to 40 mV. B, Normalized peak current-voltage relationship for wild-type (filled squares; n = 29), I848T (open circles; n = 27), and L858H (open triangles; n = 27) channels. C, Representative tail currents of WT, I848T, and L858H channels. Cells were held at -100 mV and depolarized to -20 mV for 0.5 msec, followed by a repolarization to -50 mV to elicit tail currents. D, Time constants for tail current deactivation at repolarization potentials ranging from -40 to -100 mV for wild-type (filled squares; n = 7), I848T (open circles; n = 7), and L858H (open triangles; n = 7) hNav1.7 channels. Time constants were obtained with single exponential fits to the deactivation phase of the currents. Error bars represent SE.
Figure 2.
Figure 2.
The I848T and L858H mutations differentially alter inactivation of hNav1.7. A, Fast inactivation kinetics as a function of voltage for wild-type (filled squares; n = 8), I848T (open circles; n = 8), and L858H (open triangles; n = 8) hNav1.7 channels. Currents elicited as described in Figure 1 A were fit with Hodgkin-Huxley type m 3h model to estimate the inactivation time constants. B, Comparison of steady-state fast inactivation for wild-type (filled squares; n = 20), I848T (open circles; n = 19), and L858H (open triangles; n = 17) hNav1.7 channels. Currents were elicited with test pulses to 0 mV after 500 msec inactivating prepulses. C, Comparison of steady-state slow inactivation for wild-type hNav1.7 (filled squares; n = 9), I848T (open circles; n = 8), and L858H (open triangles; n = 9) hNav1.7 channels. Slow inactivation was induced with 30 sec prepulses, followed by 100 msec pulses to -120 mV to allow recovery from fast inactivation. A test pulse to 0 mV for 20 msec was used to determine the fraction of current available. Error bars represent SE.
Figure 3.
Figure 3.
The I848T and L858H mutations enhance ramp currents of hNav1.7. Representative ramp currents elicited with 500 msec ramp depolarizations from -100 to 0 mV from HEK293 cells expressing wild-type, I848T, and L858H channels.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Akopian AN, Sivilotti L, Wood JN (1996) A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. Nature 379: 257-262. - PubMed
    1. Bendahhou S, Cummins TR, Kula RW, Fu YH, Ptacek LJ (2002) Impairment of slow inactivation as a common mechanism for periodic paralysis in DIIS4-S5. Neurology 58: 1266-1272. - PubMed
    1. Black JA, Dib-Hajj S, McNabola K, Jeste S, Rizzo MA, Kocsis JD, Waxman SG (1996) Spinal sensory neurons express multiple sodium channel alpha-subunit mRNAs. Mol Brain Res 43: 117-131. - PubMed
    1. Black JA, Cummins TR, Plumpton C, Chen YH, Hormuzdiar W, Clare JJ, Waxman SG (1999) Upregulation of a silent sodium channel after peripheral, but not central, nerve injury in DRG neurons. J Neurophysiol 82: 2776-2785. - PubMed
    1. Black JA, Liu S, Tanaka M, Cummins TR, Waxman SG (2004) Changes in the expression of tetrodotoxin-sensitive sodium channels within dorsal root ganglia neurons in inflammatory pain. Pain 108: 237-247. - PubMed

Publication types

Substances