A common local anesthetic receptor for benzocaine and etidocaine in voltage-gated mu1 Na+ channels

Pflugers Arch. 1998 Jan;435(2):293-302. doi: 10.1007/s004240050515.


According to Hille's modulated receptor hypothesis, benzocaine shares a common receptor with all other local anesthetics (LAs) in the voltage-gated Na+ channel. We tested this single receptor hypothesis using mutant muscle Na+ channels of mu1-I1575A, F1579A, and N1584A transiently expressed in Hek-293t cells. Both benzocaine and etidocaine are more effective at blocking mu1-N1584A current than the wild-type current, while they are less potent at blocking mu1-F1579A current. Such concurrent changes of both benzocaine and etidocaine potency towards F1579A and N1584A mutants suggest that they share a common LA receptor. Consistent with results found in studies of native Na+ channels, permanently charged QX-314 at 1 mM is not effective at blocking wild-type, F1579A, and N1584A current via external application. In contrast, QX-314 is relatively potent at blocking I1575A current when applied externally. This increased potency of external QX-314 against the mu1-I1575A mutant has been reported previously in a study of the brain counterpart. Mutant I1575A also appears to be highly sensitive to the external divalent cation Cd2+, probably because of the presence of cysteine residues near the mu1-I1575 position in the IV-S6 segment. To our surprise, neutral benzocaine becomes more effective at blocking mu1-I1575A current than the wild-type current, whereas the opposite is found for etidocaine. We hypothesize that an increase in accessibility of external QX-314 to the mu1-I1575A mutant is accompanied by a reduction of binding towards the charged amine component.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Anesthetics, Local / metabolism
  • Anesthetics, Local / pharmacology*
  • Benzocaine / metabolism
  • Benzocaine / pharmacology*
  • Cell Line
  • Electric Conductivity
  • Embryo, Mammalian
  • Etidocaine / metabolism
  • Etidocaine / pharmacology*
  • Humans
  • Kidney
  • Lidocaine / analogs & derivatives
  • Lidocaine / pharmacology
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Receptors, Drug / analysis*
  • Receptors, Drug / chemistry
  • Receptors, Drug / metabolism
  • Sodium Channels / chemistry*
  • Sodium Channels / drug effects*
  • Sodium Channels / genetics


  • Anesthetics, Local
  • Receptors, Drug
  • Sodium Channels
  • QX-314
  • Lidocaine
  • Etidocaine
  • Benzocaine