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, 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.
Department of Pharmacology and Toxicology and Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Indiana 46202, and.
Zhi-Yong
ZY
Tan
Lilly Research Laboratories, Indianapolis, Indiana 46285.
Andrew D
AD
Piekarz
Lilly Research Laboratories, Indianapolis, Indiana 46285.
Birgit T
BT
Priest
Lilly Research Laboratories, Indianapolis, Indiana 46285.
Kelly L
KL
Knopp
Lilly Research Laboratories, Indianapolis, Indiana 46285.
Jeffrey L
JL
Krajewski
Lilly Research Laboratories, Indianapolis, Indiana 46285.
Jeff S
JS
McDermott
Lilly Research Laboratories, Indianapolis, Indiana 46285.
Eric S
ES
Nisenbaum
Department of Pharmacology and Toxicology and Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Indiana 46202, and trcummin@iu.edu.
Theodore R
TR
Cummins
D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D001703:Biophysics; D002478:Cells, Cultured; D004558:Electric Stimulation; D005663:Furans / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000166:cytology; D047468:Immunoprecipitation; D018836:Inflammation Mediators / Q000494:pharmacology*; D008012:Lidocaine / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects*; D062559:NAV1.8 Voltage-Gated Sodium Channel / Q000737:chemistry / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000494:pharmacology; D021122:Protein Subunits / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000187:drug effects* / Q000502:physiology*; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D013779:Tetrodotoxin / Q000494:pharmacology*
C520740:A 803467; D000814:Aniline Compounds; D005663:Furans; D018836:Inflammation Mediators; D062559:NAV1.8 Voltage-Gated Sodium Channel; D010455:Peptides; D021122:Protein Subunits; C568319:Scn10a protein, rat; D026941:Sodium Channel Blockers; D013779:Tetrodotoxin; D008012:Lidocaine
action potential; hyperexcitability; nociceptor; resurgent sodium current; sodium current; voltage clamp