Nav1.7 mutations associated with paroxysmal extreme pain disorder, but not erythromelalgia, enhance Navbeta4 peptide-mediated resurgent sodium currents.
Abnormal pain sensitivity associated with inherited and acquired pain disorders occurs through increased excitability of peripheral sensory neurons in part due to changes in the properties of voltage-gated sodium channels (Navs). Resurgent sodium currents (I(NaR)) are atypical currents believed to be associated with increased excitability of neurons and may have implications in pain. Mutations in Nav1.7 (peripheral Nav isoform) associated with two genetic pain disorders, inherited erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEPD), enhance Nav1.7 function via distinct mechanisms. We show that changes in Nav1.7 function due to mutations associated with PEPD, but not IEM, are important in I(NaR) generation, suggesting that I(NaR) may play a role in pain associated with PEPD. This knowledge provides us with a better understanding of the mechanism of I(NaR) generation and may lead to the development of specialized treatment for pain disorders associated with I(NaR).
Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Jonathan W
JW
Theile
Brian W
BW
Jarecki
Andrew D
AD
Piekarz
Theodore R
TR
Cummins
D019943:Amino Acid Substitution / Q000502:physiology; D055724:Electrophysiological Phenomena / Q000502:physiology*; D004916:Erythromelalgia / Q000235:genetics / Q000503:physiopathology*; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology*; D008564:Membrane Potentials / Q000502:physiology; D020125:Mutation, Missense / Q000502:physiology*; D062556:NAV1.7 Voltage-Gated Sodium Channel; D009437:Neuralgia / Q000235:genetics / Q000503:physiopathology*; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000502:physiology; D015222:Sodium Channels / Q000502:physiology*; D014162:Transfection; D062585:Voltage-Gated Sodium Channel beta-4 Subunit
D062556:NAV1.7 Voltage-Gated Sodium Channel; D010446:Peptide Fragments; C477263:SCN4B protein, human; C486866:SCN9A protein, human; D015222:Sodium Channels; D062585:Voltage-Gated Sodium Channel beta-4 Subunit