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Biophysical Journal 85:911-920 (2003)
© 2003 The Biophysical Society

Tryptophan Scanning of D1S6 and D4S6 C-Termini in Voltage-Gated Sodium Channels

Sho-Ya Wang *, Kaitlin Bonner *, Corinna Russell {dagger} and Ging Kuo Wang {dagger}

* Department of Biology, State University of New York at Albany, Albany, New York; and {dagger} Department of Anesthesia, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts

Correspondence: Address reprint requests to Dr. Ging Kuo Wang, Dept. of Anesthesia, Brigham and Women's Hospital, 75 Francis St., Boston, MA 02115. Tel.: 617-732-6886; Fax: 617-730-2801; E-mail: wang{at}zeus.bwh.harvard.edu.

Recent reports suggest that four S6 C-termini may jointly close the voltage-gated cation channel at the cytoplasmic side, probably as an inverted teepee structure. In this study we substituted individually a total of 18 residues at D1S6 and D4S6 C-terminal ends of the rNav1.4 Na+ channel {alpha}-subunit with tryptophan (W) and examined their corresponding gating properties when expressed in Hek293t cells along with ß1 subunit. Several W-mutants displayed significant changes in activation, fast inactivation, and/or slow inactivation gating. In particular, five S6 W-mutants showed incomplete fast inactivation with noninactivating maintained currents present. Cysteine (C) substitutions of these five residues resulted in two mutants with slightly more maintained currents. Multiple substitutions at these five positions yielded two mutants (L437C/A438W, L435W/L437C/A438W) that exhibited phenotypes with minimal fast inactivation. Unexpectedly, such inactivation-deficient mutants expressed Na+ currents as well as did the wild-type. Furthermore, all mutants with impaired fast inactivation exhibited an enhanced slow inactivation phenotype. Implications of these results will be discussed in terms of indirect allosteric modulations via amino acid substitutions and/or a direct involvement of S6 C-termini in Na+ channel gating.




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