Atomic determinants of state-dependent block of sodium channels by charged local anesthetics and benzocaine

FEBS Lett. 2006 Nov 13;580(26):6027-32. doi: 10.1016/j.febslet.2006.10.035. Epub 2006 Oct 24.


Molecular modeling predicts that a local anesthetic (LA) lidocaine binds to the resting and open Na(v)1.5 in different modes, interacting with LA-sensing residues known from experiments. Besides the major pathway via the open activation gate, LAs can reach the inner pore via a "sidewalk" between D3S6, D4S6, and D3P. The ammonium group of a cationic LA binds in the focus of the pore-helices macrodipoles, which also stabilize a Na(+) ion chelated by two benzocaine molecules. The LA's cationic group and a Na(+) ion in the selectivity filter repel each other suggesting that the Na(+) depletion upon slow inactivation would stabilize a LA, while a LA would stabilize slow-inactivated states.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anesthetics, Local / chemistry
  • Anesthetics, Local / pharmacokinetics*
  • Benzocaine / chemistry
  • Benzocaine / pharmacokinetics*
  • Binding Sites
  • Humans
  • Lidocaine / chemistry
  • Lidocaine / pharmacokinetics*
  • Models, Molecular*
  • Molecular Structure
  • Muscle Proteins / chemistry
  • Muscle Proteins / metabolism
  • NAV1.5 Voltage-Gated Sodium Channel
  • Protein Conformation
  • Sodium / chemistry
  • Sodium Channels / chemistry*
  • Sodium Channels / metabolism*


  • Anesthetics, Local
  • Muscle Proteins
  • NAV1.5 Voltage-Gated Sodium Channel
  • SCN5A protein, human
  • Sodium Channels
  • Lidocaine
  • Sodium
  • Benzocaine