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Institute of Pharmacology, Medical University of Vienna, Vienna, Austria (W.S., J.S., T.Z., E.Z., K.H., H.T.); Cardiac Electrophysiology Laboratories, University of Chicago, Chicago, Illinois (I.G., H.A.F.); and Division of Cardiology, Emory University, Atlanta, Georgia and Atlanta Veterans Affairs Hospital, Decatur, Georgia (S.C.D.)
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 (IUS). 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 IUS. rNaV 1.4 channels carrying the mutation K1237E in the selectivity filter were driven into IUS 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 (
rec = 171 ± 19 s), typical for recovery from IUS. After exposure to 300 µM lidocaine, the fraction of channels recovering from IUS 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 IUS, indicating that lidocaine has to bind to the inner vestibule of the channel to modulate IUS. We propose that IUS 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.
Address correspondence to: Dr. Hannes Todt, Medical University of Vienna, Institute of Pharmacology, Währingerstrasse 13A, A-1090 Vienna, Austria. E-mail: hannes.todt{at}meduniwien.ac.at
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