|
|
|
|
|
|
|
||
The Journal of General Physiology, Vol 103, 501-518, Copyright © 1994 by The Rockefeller University Press
ARTICLES |
GK Wang and SY Wang
Department of Anesthesia, Harvard Medical School, Boston, Massachusetts 02115.
Hille (1977. Journal of General Physiology. 69:497-515) first proposed a modulated receptor hypothesis (MRH) to explain the action of benzocaine in voltage-gated Na+ channels. Using the MRH as a framework, we examined benzocaine binding in batrachotoxin (BTX)-modified Na+ channels under voltage-clamp conditions using either step or ramp command signals. We found that benzocaine binding is strongly voltage dependent. At -70 mV, the concentration of benzocaine that inhibits 50% of BTX-modified Na+ currents in GH3 cells (IC50) is 0.2 mM, whereas at +50 mV, the IC50 is 1.3 mM. Dose-response curves indicate that only one molecule of benzocaine is required to bind with one BTX-modified Na+ channel at -70 mV, whereas approximately two molecules are needed at +50 mV. Upon treatment with the inactivation modifier chloramine-T, the binding affinity of benzocaine is reduced significantly at -70 mV, probably as a result of the removal of the inactivated state of BTX- modified Na+ channels. The same treatment, however, enhances the binding affinity of cocaine near this voltage. External Na+ ions appear to have little effect on benzocaine binding, although they do affect cocaine binding. We conclude that two mechanisms underlie the action of local anesthetics in BTX-modified Na+ channels. Unlike open-channel blockers such as cocaine and bupivacaine, neutral benzocaine binds preferentially with BTX-modified Na+ channels in a closed state. Furthermore, benzocaine can be modified chemically so that it behaves like an open-channel blocker. This compound also elicits a use- dependent block in unmodified Na+ channels after repetitive depolarizations, whereas benzocaine does not. The implications of these findings for the MRH theory will be discussed.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  G. M. Lipkind and H. A. Fozzard Molecular Modeling of Local Anesthetic Drug Binding by Voltage-Gated Sodium Channels Mol. Pharmacol., December 1, 2005; 68(6): 1611 - 1622. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Delpon, R. Caballero, C. Valenzuela, M. Longobardo, D. Snyders, and J. Tamargo Benzocaine enhances and inhibits the K+ current through a human cardiac cloned channel (Kv1.5) Cardiovasc Res, May 1, 1999; 42(2): 510 - 520. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Peri, D. J. Triggle, and S. Singh Regulation of L-type Calcium Channels in Pituitary GH4C1 Cells by Depolarization J. Biol. Chem., August 17, 2001; 276(34): 31667 - 31673. [Abstract] [Full Text] [PDF]
|
|
|
|
