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Charged tetracaine as an inactivation enhancer in batrachotoxin-modified Na+ channels
- Source :
- Biophysical journal. 67(5)
- Publication Year :
- 1994
-
Abstract
- Two distinct types of local anesthetics (LAs) have previously been found to block batrachotoxin (BTX)-modified Na+ channels: type 1 LAs such as cocaine and bupivacaine interact preferentially with open channels, whereas type 2 LAs, such as benzocaine and tricaine, with inactivated channels. Herein, we describe our studies of a third type of LA, represented by tetracaine as a dual blocker that binds strongly with closed channels but also binds to a lesser extent with open channels when the membrane is depolarized. Enhanced inactivation of BTX-modified Na+ channels by tetracaine was determined by steady-state inactivation measurement and by the dose-response curve. The 50% inhibitory concentration (IC50) was estimated to be 5.2 microM at -70 mV, where steady-state inactivation was maximal, with a Hill coefficient of 0.98 suggesting that one tetracaine molecule binds with one inactivated channel. Tetracaine also interacted efficiently with Na+ channels when the membrane was depolarized; the IC50 was estimated to be 39.5 microM at +50 mV with a Hill coefficient of 0.94. Unexpectedly, charged tetracaine was found to be the primary active form in the blocking of inactivated channels. In addition, external Na+ ions appeared to antagonize the tetracaine block of inactivated channels. Consistent with these results, N-butyl tetracaine quaternary ammonium, a permanently charged tetracaine derivative, remained a strong inactivation enhancer. Another derivative of tetracaine, 2-(di-methylamino) ethyl benzoate, which lacked a 4-butylamino functional group on the phenyl ring, elicited block that was approximately 100-fold weaker than that of tetracaine. We surmise that 1) the binding site for inactivation enhancers is within the Na+ permeation pathway, 2) external Na+ ions antagonize the block of inactivation enhancers by electrostatic repulsion, 3) the 4-butylamino functional group on the phenyl ring is critical for block and for the enhancement of inactivation, and 4) there are probably overlapping binding sites for both inactivation enhancers and open-channel blockers within the Na+ pore.
- Subjects :
- Tetracaine
Stereochemistry
Sodium
Biophysics
chemistry.chemical_element
In Vitro Techniques
Biophysical Phenomena
Sodium Channels
Membrane Potentials
chemistry.chemical_compound
Sodium channel blocker
medicine
Electrochemistry
Animals
Binding site
Batrachotoxins
Membrane potential
Binding Sites
Chemistry
Sodium channel
Hydrogen-Ion Concentration
Clone Cells
Rats
Kinetics
Membrane
Batrachotoxin
medicine.drug
Sodium Channel Blockers
Research Article
Subjects
Details
- ISSN :
- 00063495
- Volume :
- 67
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- Biophysical journal
- Accession number :
- edsair.doi.dedup.....737045dafbcc5271f4a4207afb89d863