Batrachotoxin (BTX)-activated Na+ channels from rabbit skeletal muscle were incorporated into planar lipid bilayers. These channels appear to open most of the time at voltages greater than -60 mV. Local anesthetics, including QX-314, bupivacaine, and cocaine when applied internally, induce different durations of channel closures and can be characterized as "fast" (mean closed duration less than 10 ms at +50 mV), "intermediate" (approximately 80 ms), and "slow" (approximately 400 ms) blockers, respectively. The action of these local anesthetics on the Na+ channel is voltage dependent; larger depolarizations give rise to stronger binding interactions. Both the dose-response curve and the kinetics of the cocaine-induced closures indicate that there is a single class of cocaine-binding site. QX-314, though a quaternary-amine local anesthetic, apparently competes with the same binding site. External cocaine or bupivacaine application is almost as effective as internal application, whereas external QX-314 is ineffective. Interestingly, external Na+ ions reduce the cocaine binding affinity drastically, whereas internal Na+ ions have little effect. Both the cocaine association and dissociation rate constants are altered when external Na+ ion concentrations are raised. We conclude that (a) one cocaine molecule closes one BTX-activated Na+ channel in an all-or-none manner, (b) the binding affinity of cocaine is voltage sensitive, (c) this cocaine binding site can be reached by a hydrophilic pathway through internal surface and by a hydrophobic pathway through bilayer membrane, and (d) that this binding site interacts indirectly with the Na+ ions. A direct interaction between the receptor and Na+ ions seems minimal.
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Article| December 01 1988
Cocaine-induced closures of single batrachotoxin-activated Na+ channels in planar lipid bilayers.
G K Wang
Department of Anesthesia Research Laboratories, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts 02115.
Online Issn: 1540-7748
Print Issn: 0022-1295
J Gen Physiol (1988) 92 (6): 747–765.
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G K Wang; Cocaine-induced closures of single batrachotoxin-activated Na+ channels in planar lipid bilayers.. J Gen Physiol 1 December 1988; 92 (6): 747–765. doi: https://doi.org/10.1085/jgp.92.6.747
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