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Research ArticleArticle

How Batrachotoxin Modifies the Sodium Channel Permeation Pathway: Computer Modeling and Site-Directed Mutagenesis

Sho-Ya Wang, Jane Mitchell, Denis B. Tikhonov, Boris S. Zhorov and Ging Kuo Wang
Molecular Pharmacology March 2006, 69 (3) 788-795; DOI: https://doi.org/10.1124/mol.105.018200
Sho-Ya Wang
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Jane Mitchell
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Denis B. Tikhonov
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Boris S. Zhorov
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Ging Kuo Wang
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Abstract

A structural model of the rNav1.4 Na+ channel with batrachotoxin (BTX) bound within the inner cavity suggested that the BTX pyrrole moiety is located between a lysine residue at the DEKA selectivity filter (Lys1237) and an adjacent phenylalanine residue (Phe1236). We tested this pyrrole-binding model by site-directed mutagenesis of Phe1236 at D3/P-loop with 11 amino acids. Mutants F1236D and F1236E expressed poorly, whereas nine other mutants either expressed robust Na+ currents, like the wild-type (F1236Y/Q/K), or somewhat reduced current (F1236G/A/C/N/W/R). Gating properties were altered modestly in most mutant channels, with F1236G displaying the greatest shift in activation and steady-state fast inactivation (-10.1 and -7.5 mV, respectively). Mutants F1236K and F1236R were severely resistant to BTX after 1000 repetitive pulses (+50 mV/20 ms at 2 Hz), whereas seven other mutants were sensitive but with reduced magnitudes compared with the wild type. It is noteworthy that rNav1.4-F1236K mutant Na+ channels remained highly sensitive to block by the local anesthetic bupivacaine, unlike several other BTX-resistant mutant channels. Our data thus support a model in which BTX, when bound within the inner cavity, interacts with the D3/P-loop directly. Such a direct interaction provides clues on how BTX alters the Na+ channel selectivity and conductance.

  • Received August 23, 2005.
  • Accepted December 13, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 69 (3)
Molecular Pharmacology
Vol. 69, Issue 3
1 Mar 2006
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Research ArticleArticle

How Batrachotoxin Modifies the Sodium Channel Permeation Pathway: Computer Modeling and Site-Directed Mutagenesis

Sho-Ya Wang, Jane Mitchell, Denis B. Tikhonov, Boris S. Zhorov and Ging Kuo Wang
Molecular Pharmacology March 1, 2006, 69 (3) 788-795; DOI: https://doi.org/10.1124/mol.105.018200

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Research ArticleArticle

How Batrachotoxin Modifies the Sodium Channel Permeation Pathway: Computer Modeling and Site-Directed Mutagenesis

Sho-Ya Wang, Jane Mitchell, Denis B. Tikhonov, Boris S. Zhorov and Ging Kuo Wang
Molecular Pharmacology March 1, 2006, 69 (3) 788-795; DOI: https://doi.org/10.1124/mol.105.018200
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