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J. Biol. Chem., Vol. 276, Issue 30, 27831-27839, July 27, 2001
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From the Amino acids located in the outer
vestibule of the voltage-gated Na+ channel determine
the permeation properties of the channel. Recently, residues lining the
outer pore have also been implicated in channel gating. The domain (D)
IV P-loop residue alanine 1529 forms a part of the putative selectivity
filter of the adult rat skeletal muscle (µ1) Na+ channel.
Here we report that replacement of alanine 1529 by aspartic acid
enhances entry to an ultra-slow inactivated state. Ultra-slow inactivation is characterized by recovery time constants on the order
of ~100 s from prolonged depolarizations and by the fact that entry
to this state can be reduced by binding to the pore of a mutant
µ-conotoxin GIIIA, suggesting that ultra-slow inactivation may
reflect a structural rearrangement of the outer vestibule. The voltage
dependence of ultra-slow inactivation in DIV-A1529D is U-shaped,
with a local maximum near
The Selectivity Filter of the Voltage-gated Sodium Channel Is
Involved in Channel Activation*
,,,,
,
Institute of Pharmacology, University of
Vienna, 1090 Vienna, Austria, the ** Division of Cardiology, Emory
University, Atlanta, Georgia 30033, the Atlanta Veterans
Administration Hospital, Decatur, Georgia 30033, the ¶ Department
of Physiology and Biophysics, University of Calgary, Calgary T2N 4N1,
Canada, and the § Cardiac Electrophysiology Laboratories,
The University of Chicago, Chicago, Illinois 60637
60 mV, whereas activation is maximal only
above 20 mV. Furthermore, a train of brief depolarizations produces
more ultra-slow inactivation than a single maintained depolarization of
the same duration. These data suggest that ultra-slow inactivation
emanates from "partially activated" closed states and that the
P-loop in DIV may undergo a conformational change during channel
activation, which is accentuated by DIV-A1529D.
*
This work was supported by National Institutes of Health
Grant HL-P01-20592 (to H. A. F.), by funds from the
Max Kade Foundation, Inc., New York (to H. T.), by Grant
P13961-MED from the Fonds zur Förderung der Wissenschaftlichen
Forschung (to H. T.), by an American Heart Association Southeast
Affiliate Beginning Grant-in-Aid (to S. C. D.), by a
Scientist Development Award from the American Heart Association (to
S. C. D.), by a Procter and Gamble University Research Exploratory
Award (to S. C. D.), by National Institutes of Health Grant HL64828
(to H. A. F.), and by funds from the Canadian Institutes of Health
Research.The costs of publication of this article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Canadian Institutes of Health Research Distinguished Scientist
and a Medical Scientist of the Alberta Heritage Foundation for Medical Research.
To whom correspondence should be addressed: Inst. of
Pharmacology, University of Vienna, Währingerstrasse 13A, A-1090
Vienna, Austria. Tel.: 43-1-4277-64120; E-mail:
hannes.todt@univie.ac.at.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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