Slow closed-state inactivation: A novel mechanism underlying ramp currents in cells expressing the hNE/PN1 sodium channel

Theodore R. Cummins, James R. Howe, Stephen G. Waxman

Research output: Contribution to journalArticle

290 Scopus citations


To better understand why sensory neurons express voltage-gated Na+ channel isoforms that are different from those expressed in other types of excitable cells, we compared the properties of the hNE sodium channel [a human homolog of PN1, which is selectively expressed in dorsal root ganglion (DRG) neurons] with that of the skeletal muscle Na+ channel (hSkM1) [both expressed in human embryonic kidney (HEK293) cells]. Although the voltage dependence of activation was similar, the inactivation properties were different. The V 1/2 for steady-state inactivation was slightly more negative, and the rate of open-state inactivation was ~ 50% slower for hNE. However, the greatest difference was that closed-state inactivation and recovery from inactivation were up to fivefold slower for hNE than for hSkM1 channels. TTX- sensitive (TTX-S) currents in small DRG neurons also have slow closed-state inactivation, suggesting that hNE/PN1 contributes to this TTX-S current. Slow ramp depolarizations (0.25 mV/msec) elicited TTX-S persistent currents in cells expressing hNE channels, and in DRG neurons, but not in cells expressing hSkM1 channels. We propose that slow closed-state inactivation underlies these ramp currents. This conclusion is supported by data showing that divalent cations such as Cd2+ and Zn2+ (50-200 μM) slowed closed- state inactivation and also dramatically increased the ramp currents for DRG TTX-S currents and hNE channels but not for hSkM1 channels. The hNE and DRG TTX-S ramp currents activated near -65 mV and therefore could play an important role in boosting stimulus depolarizations in sensory neurons. These results suggest that differences in the kinetics of closed-state inactivation may confer distinct integrative properties on different Na+ channel isoforms.

Original languageEnglish (US)
Pages (from-to)9607-9619
Number of pages13
JournalJournal of Neuroscience
Issue number23
StatePublished - Dec 1 1998
Externally publishedYes


  • Dorsal root ganglion
  • Excitability
  • Expression
  • Persistent current
  • Sodium channel
  • Tetrodotoxin

ASJC Scopus subject areas

  • Neuroscience(all)

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