Tetrodotoxin-resistant sodium channels in sensory neurons generate slow resurgent currents that are enhanced by inflammatory mediators

Resurgent sodium currents contribute to the regeneration of action potentials and enhanced neuronal excitability. Tetrodotoxin-sensitive (TTX-S) resurgent currents have been described in many different neuron populations, including cerebellar and dorsal root ganglia (DRG) neurons. In most cases, sod...

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Bibliographic Details
Published in:The Journal of neuroscience 2014-05, Vol.34 (21), p.7190-7197
Main Authors: Tan, Zhi-Yong, Piekarz, Andrew D, Priest, Birgit T, Knopp, Kelly L, Krajewski, Jeffrey L, McDermott, Jeff S, Nisenbaum, Eric S, Cummins, Theodore R
Format: Article
Language:English
Subjects:
Aniline Compounds - pharmacology
Animals
Biophysics
Cells, Cultured
Electric Stimulation
Furans - pharmacology
Ganglia, Spinal - cytology
Immunoprecipitation
Inflammation Mediators - pharmacology
Lidocaine - pharmacology
Membrane Potentials - drug effects
NAV1.8 Voltage-Gated Sodium Channel - chemistry
NAV1.8 Voltage-Gated Sodium Channel - metabolism
Patch-Clamp Techniques
Peptides - pharmacology
Protein Subunits - metabolism
Rats
Rats, Sprague-Dawley
Sensory Receptor Cells - drug effects
Sensory Receptor Cells - physiology
Sodium Channel Blockers - pharmacology
Tetrodotoxin - pharmacology
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Summary:Resurgent sodium currents contribute to the regeneration of action potentials and enhanced neuronal excitability. Tetrodotoxin-sensitive (TTX-S) resurgent currents have been described in many different neuron populations, including cerebellar and dorsal root ganglia (DRG) neurons. In most cases, sodium channel Nav1.6 is the major contributor to these TTX-S resurgent currents. Here we report a novel TTX-resistant (TTX-R) resurgent current recorded from rat DRG neurons. The TTX-R resurgent currents are similar to classic TTX-S resurgent currents in many respects, but not all. As with TTX-S resurgent currents, they are activated by membrane repolarization, inhibited by lidocaine, and enhanced by a peptide-mimetic of the β4 sodium channel subunit intracellular domain. However, the TTX-R resurgent currents exhibit much slower kinetics, occur at more depolarized voltages, and are sensitive to the Nav1.8 blocker A803467. Moreover, coimmunoprecipitation experiments from rat DRG lysates indicate the endogenous sodium channel β4 subunits associate with Nav1.8 in DRG neurons. These results suggest that slow TTX-R resurgent currents in DRG neurons are mediated by Nav1.8 and are generated by the same mechanism underlying TTX-S resurgent currents. We also show that both TTX-S and TTX-R resurgent currents in DRG neurons are enhanced by inflammatory mediators. Furthermore, the β4 peptide increased excitability of small DRG neurons in the presence of TTX. We propose that these slow TTX-R resurgent currents contribute to the membrane excitability of nociceptive DRG neurons under normal conditions and that enhancement of both types of resurgent currents by inflammatory mediators could contribute to sensory neuronal hyperexcitability associated with inflammatory pain.
ISSN:0270-6474
1529-2401
DOI:10.1523/JNEUROSCI.5011-13.2014