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Tryptophan Substitution of a Putative D4S6 Gating Hinge Alters Slow Inactivation in Cardiac Sodium Channels

Sho-Ya Wang ^*, Corinna Russell  and Ging Kuo Wang 

^* Department of Biology, State University of New York, Albany, New York 12222; and Department of Anesthesia, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115

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

Voltage-gated Na⁺ channels display rapid activation gating (opening) as well as fast and slow inactivation gating (closing) during depolarization. We substituted residue S1759 (serine), a putative D4S6 gating hinge of human cardiac hNav1.5 Na⁺ channels with A (alanine), D (aspartate), K (lysine), L (leucine), P (proline), and W (tryptophan). Significant shifts in gating parameters for activation and steady-state fast inactivation were observed in A-, D-, K-, and W-substituted mutant Na⁺ channels. No gating shifts occurred in the L-substituted mutant, whereas the P-substituted mutant did not yield sufficient Na⁺ currents. Wild-type, A-, D-, and L-substituted mutant Na⁺ channels showed little or no slow inactivation with a 10-s conditioning pulse ranging from –180 to 0 mV. Unexpectedly, W- and K-substituted mutant Na⁺ channels displayed profound maximal slow inactivation around –100 mV (85% and 70%, respectively). However, slow inactivation was progressively reversed in magnitude from –70 to 0 mV. This regression was minimized in inactivation-deficient hNav1.5-S1759W/L409C/A410W Na⁺ channels, indicating that the intracellular fast-inactivation gate caused such a reversal. Our data suggest that the hNav1.5-S1759 residue plays a critical role in slow inactivation. Possible mechanisms for S1759 involvement in slow inactivation and for antagonism between fast and slow inactivation are discussed.

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