ISSN:
1432-2013
Keywords:
Key words Local anesthetics
;
Benzocaine
;
Single receptor hypothesis
;
Mutant muscle Na+ channels
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
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 μ1-I1575A, F1579A, and N1584A transiently expressed in Hek-293t cells. Both benzocaine and etidocaine are more effective at blocking μ1-N1584A current than the wild-type current, while they are less potent at blocking μ1-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 μ1-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 μ1-I1575 position in the IV-S6 segment. To our surprise, neutral benzocaine becomes more effective at blocking μ1-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 μ1-I1575A mutant is accompanied by a reduction of binding towards the charged amine component.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/s004240050515
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