Local anesthetics disrupt energetic coupling between the voltage-sensing segments of a sodium channel

J Gen Physiol. 2009 Jan;133(1):1-15. doi: 10.1085/jgp.200810103. Epub 2008 Dec 15.


Local anesthetics block sodium channels in a state-dependent fashion, binding with higher affinity to open and/or inactivated states. Gating current measurements show that local anesthetics immobilize a fraction of the gating charge, suggesting that the movement of voltage sensors is modified when a local anesthetic binds to the pore of the sodium channel. Here, using voltage clamp fluorescence measurements, we provide a quantitative description of the effect of local anesthetics on the steady-state behavior of the voltage-sensing segments of a sodium channel. Lidocaine and QX-314 shifted the midpoints of the fluorescence-voltage (F-V) curves of S4 domain III in the hyperpolarizing direction by 57 and 65 mV, respectively. A single mutation in the S6 of domain IV (F1579A), a site critical for local anesthetic block, abolished the effect of QX-314 on the voltage sensor of domain III. Both local anesthetics modestly shifted the F-V relationships of S4 domain IV toward hyperpolarized potentials. In contrast, the F-V curve of the S4 domain I was shifted by 11 mV in the depolarizing direction upon QX-314 binding. These antagonistic effects of the local anesthetic indicate that the drug modifies the coupling between the voltage-sensing domains of the sodium channel. Our findings suggest a novel role of local anesthetics in modulating the gating apparatus of the sodium channel.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anesthesia, Local
  • Anesthetics, Local / pharmacology*
  • Animals
  • Kinetics
  • Lidocaine / analogs & derivatives*
  • Lidocaine / pharmacology*
  • Models, Biological
  • Muscle Proteins / drug effects
  • Muscle Proteins / physiology
  • Patch-Clamp Techniques
  • Protein Structure, Tertiary
  • Rats
  • Sodium Channel Blockers / pharmacology*
  • Sodium Channels / drug effects*
  • Sodium Channels / physiology*
  • Xenopus


  • Anesthetics, Local
  • Muscle Proteins
  • Scn4a protein, rat
  • Sodium Channel Blockers
  • Sodium Channels
  • QX-314
  • Lidocaine