The Selectivity Filter of the Voltage-gated Sodium Channel is Involved in Channel Activation

Karlheinz Hilber, Walter Sandtner, Oliver Kudlacek, Ian W. Glaaser, Eva Weisz, John W. Kyle, Robert J. French, Harry A. Fozzard, Samuel C. Dudley, Hannes Todt

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Abstract

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 ultraslow 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 -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.

Original languageEnglish (US)
Pages (from-to)27831-27839
Number of pages9
JournalJournal of Biological Chemistry
Volume276
Issue number30
DOIs
StatePublished - Jul 27 2001

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    Hilber, K., Sandtner, W., Kudlacek, O., Glaaser, I. W., Weisz, E., Kyle, J. W., French, R. J., Fozzard, H. A., Dudley, S. C., & Todt, H. (2001). The Selectivity Filter of the Voltage-gated Sodium Channel is Involved in Channel Activation. Journal of Biological Chemistry, 276(30), 27831-27839. https://doi.org/10.1074/jbc.M101933200