Lidocaine: a foot in the door of the inner vestibule prevents ultra-slow inactivation of a voltage-gated sodium channel.
After opening, Na(+) channels may enter several kinetically distinct inactivated states. Whereas fast inactivation occurs by occlusion of the inner channel pore by the fast inactivation gate, the mechanistic basis of slower inactivated states is much less clear. We have recently suggested that the inner pore of the voltage-gated Na(+) channel may be involved in the process of ultra-slow inactivation (I(US)). The local anesthetic drug lidocaine is known to bind to the inner vestibule of the channel and to interact with slow inactivated states. We therefore sought to explore the effect of lidocaine binding on I(US). rNa(V) 1.4 channels carrying the mutation K1237E in the selectivity filter were driven into I(US) by long depolarizing pulses (-20 mV, 300 s). After repolarization to -120 mV, 53 +/- 5% of the channels recovered with a very slow time constant (tau(rec) = 171 +/- 19 s), typical for recovery from I(US). After exposure to 300 microM lidocaine, the fraction of channels recovering from I(US) was reduced to 13 +/- 4% (P < 0.01, n = 6). An additional mutation in the binding site of lidocaine (K1237E + F1579A) substantially reduced the effect of lidocaine on I(US), indicating that lidocaine has to bind to the inner vestibule of the channel to modulate I(US). We propose that I(US) involves a closure of the inner vestibule of the channel. Lidocaine may interfere with this pore motion by acting as a "foot in the door" in the inner vestibule.
Medical University of Vienna, Institute of Pharmacology, Währingerstrasse 13A, A-1090 Vienna, Austria.
Walter
W
Sandtner
Julia
J
Szendroedi
Touran
T
Zarrabi
Eva
E
Zebedin
Karlheinz
K
Hilber
Ian
I
Glaaser
Harry A
HA
Fozzard
Samuel C
SC
Dudley
Hannes
H
Todt
D019943:Amino Acid Substitution; D000818:Animals; D001665:Binding Sites; D004594:Electrophysiology; D018698:Glutamic Acid / Q000235:genetics; D008012:Lidocaine / Q000494:pharmacology*; D008239:Lysine / Q000235:genetics; D016297:Mutagenesis, Site-Directed; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D015222:Sodium Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D014982:Xenopus laevis
D026941:Sodium Channel Blockers; D015222:Sodium Channels; D018698:Glutamic Acid; D008012:Lidocaine; D008239:Lysine