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Molecular Pharmacology

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Novel Molecular Determinants in the Pore Region of Sodium Channels Regulate Local Anesthetic Binding

Toshio Yamagishi, Wei Xiong, Andre Kondratiev, Patricio Vélez, Ailsa Méndez-Fitzwilliam, Jeffrey R. Balser, Eduardo Marbán and Gordon F. Tomaselli
Molecular Pharmacology October 2009, 76 (4) 861-871; DOI: https://doi.org/10.1124/mol.109.055863
Toshio Yamagishi
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Wei Xiong
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Andre Kondratiev
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Patricio Vélez
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Ailsa Méndez-Fitzwilliam
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Jeffrey R. Balser
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Eduardo Marbán
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Gordon F. Tomaselli
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Abstract

The pore of the Na+ channel is lined by asymmetric loops formed by the linkers between the fifth and sixth transmembrane segments (S5-S6). We investigated the role of the N-terminal portion (SS1) of the S5-S6 linkers in channel gating and local anesthetic (LA) block using site-directed cysteine mutagenesis of the rat skeletal muscle (NaV1.4) channel. The mutants examined have variable effects on voltage dependence and kinetics of fast inactivation. Of the cysteine mutants immediately N-terminal to the putative DEKA selectivity filter in four domains, only Q399C in domain I and F1236C in domain III exhibit reduced use-dependent block. These two mutations also markedly accelerated the recovery from use-dependent block. Moreover, F1236C and Q399C significantly decreased the affinity of QX-314 for binding to its channel receptor by 8.5- and 3.3-fold, respectively. Oddly enough, F1236C enhanced stabilization of slow inactivation by both hastening entry into and delaying recovery from slow inactivation states. It is noteworthy that symmetric applications of QX-314 on both external and internal sides of F1236C mutant channels reduced recovery from use-dependent block, indicating an allosteric effect of external QX-314 binding on the recovery of availability of F1236C. These observations suggest that cysteine mutation in the SS1 region, particularly immediate adjacent to the DEKA ring, may lead to a structural rearrangement that alters binding of permanently charged QX-314 to its receptor. The results lend further support for a role for the selectivity filter region as a structural determinant for local anesthetic block.

  • P segment, pore-lining segment
  • LA, local anesthetic
  • QX-314, N-(2,6-dimethylphenylcarbamoylmethyl)triethylammonium bromide
  • MTS, methanethiosulfonate
  • WT, wild type.

Footnotes

  • The work was supported by the National Institutes of Health National Heart, Lung, and Blood Institute [Grants R01-HL50411, R01-HL52768] (to G.F.T. and E.M., respectively). G.F.T. is the Michel Mirowski Professor of Cardiology at Johns Hopkins.

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

  • ABBREVIATIONS:

  • T.Y. and W.X. contributed equally to this work.

    • Received February 25, 2009.
    • Accepted June 26, 2009.
  • © 2009 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 76 (4)
Molecular Pharmacology
Vol. 76, Issue 4
October 2009
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Novel Molecular Determinants in the Pore Region of Sodium Channels Regulate Local Anesthetic Binding

Toshio Yamagishi, Wei Xiong, Andre Kondratiev, Patricio Vélez, Ailsa Méndez-Fitzwilliam, Jeffrey R. Balser, Eduardo Marbán and Gordon F. Tomaselli
Molecular Pharmacology October 1, 2009, 76 (4) 861-871; DOI: https://doi.org/10.1124/mol.109.055863

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Novel Molecular Determinants in the Pore Region of Sodium Channels Regulate Local Anesthetic Binding

Toshio Yamagishi, Wei Xiong, Andre Kondratiev, Patricio Vélez, Ailsa Méndez-Fitzwilliam, Jeffrey R. Balser, Eduardo Marbán and Gordon F. Tomaselli
Molecular Pharmacology October 1, 2009, 76 (4) 861-871; DOI: https://doi.org/10.1124/mol.109.055863
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