Inactivation gating determines nicotine blockade of human HERG channels.

  • Wang H
  • Shi H
  • Liao S
 et al. 
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We have previously found that nicotine blocked multiple K+ currents, including the rapid component of delayed rectifier K+ currents (IKr), by interacting directly with the channels. To shed some light on the mechanisms of interaction between nicotine and channels, we performed detailed analysis on the human ether-à-go-go-related gene (HERG) channels, which are believed to be equivalent to the native I(Kr) when expressed in Xenopus oocytes. Nicotine suppressed the HERG channels in a concentration-dependent manner with greater potency with voltage protocols, which favor channel inactivation. Nicotine caused dramatic shifts of the voltage-dependent inactivation curve to more negative potentials and accelerated the inactivation process. Conversely, maneuvers that weakened the channel inactivation gating considerably relieved the blockade. Elevating the extracellular K+ concentration from 5 to 20 mM increased the nicotine concentration (by approximately 100-fold) needed to achieve the same degree of inhibition. Moreover, nicotine lost its ability to block the HERG channels when a single mutation was introduced to a residue located after transmembrane domain 6 (S631A) to remove the rapid channel inactivation. Our data suggest that the inactivation gating determines nicotine blockade of the HERG channels.

Author-supplied keywords

  • Animals
  • Cation Transport Proteins
  • DNA-Binding Proteins
  • Dose-Response Relationship, Drug
  • Ether-A-Go-Go Potassium Channels
  • Humans
  • Ion Channel Gating
  • Ion Channel Gating: drug effects
  • Ion Channel Gating: physiology
  • Nicotine
  • Nicotine: pharmacology
  • Nicotinic Agonists
  • Nicotinic Agonists: pharmacology
  • Patch-Clamp Techniques
  • Potassium Channels
  • Potassium Channels, Voltage-Gated
  • Potassium Channels: physiology
  • Trans-Activators
  • Xenopus laevis

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  • H Z Wang

  • H Shi

  • S J Liao

  • Z Wang

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