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Biophys J, February 2000, p. 773-784, Vol. 78, No. 2

A Point Mutation in Domain 4-Segment 6 of the Skeletal Muscle Sodium Channel Produces an Atypical Inactivation State

John P. O'Reilly,* Sho-Ya Wang,dagger and Ging Kuo Wang*

 *Department of Anesthesia Research, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, and  dagger Department of Biological Sciences, State University of New York at Albany, Albany, New York 12222 USA

We compared wild-type rat skeletal muscle NaChs (µ1) and a mutant NaCh (Y1586K) that has a single amino acid substitution, lysine (K) for tyrosine (Y), at position 1586 in the S6 transmembrane segment of domain 4. In Y1586K, macroscopic current decay is faster, the V1/2 of the activation curve is shifted in the depolarized direction, and the fast-inactivation curve is less steep compared with µ1. After an 8-ms depolarization pulse, Y1586K recovers from inactivation much more slowly than µ1. The recovery is double exponential, suggesting recovery from two inactivation states. Varying the depolarization protocols isolates entry into an additional, "atypical" inactivation state in Y1586K that is distinct from typical fast or slow inactivation. Substitution of positively charged arginine (R) at Y1586 produces an inactivation phenotype similar to that of Y1586K. Substitution by negatively charged aspartic acid (D) or uncharged alanine (A) at Y1586 produces an inactivation phenotype similar to µ1. Our results suggest that the positive charge of lysine (K) produces the atypical inactivation state in Y1586K. We propose that a conformational change during depolarization alters the relative position of the 1586K residue in the D4-S6 segment and that atypical inactivation in Y1586K occurs via an electrostatic interaction in or near the inner pore region.

Biophys J, February 2000, p. 773-784, Vol. 78, No. 2
© 2000 by the Biophysical Society   0006-3495/00/02/773/12  $2.00


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