title: A common local anesthetic receptor for benzocaine and etidocaine in voltage-gated mu1 Na+ channels.
abstract: 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.
authors.affiliation: Department of Anesthesia, Brigham and Women's Hospital, 75 Francis St. Boston, MA 02115, USA.
authors.forename: G K
authors.initials: GK
authors.lastname: Wang
authors.forename: C
authors.initials: C
authors.lastname: Quan
authors.forename: S
authors.initials: S
authors.lastname: Wang
mesh_terms: D000595:Amino Acid Sequence; D000779:Anesthetics, Local / Q000378:metabolism / Q000494:pharmacology*; D001566:Benzocaine / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D004553:Electric Conductivity; D004622:Embryo, Mammalian; D005041:Etidocaine / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007668:Kidney; D008012:Lidocaine / Q000031:analogs & derivatives / Q000494:pharmacology; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011955:Receptors, Drug / Q000032:analysis* / Q000737:chemistry / Q000378:metabolism; D015222:Sodium Channels / Q000737:chemistry* / Q000187:drug effects* / Q000235:genetics
chemical_list: D000779:Anesthetics, Local; D011955:Receptors, Drug; D015222:Sodium Channels; C012647:QX-314; D008012:Lidocaine; D005041:Etidocaine; D001566:Benzocaine