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Research ArticleArticle

Local Anesthetic Block of Kv Channels: Role of the S6 Helix and the S5-S6 Linker for Bupivacaine Action

Johanna Nilsson, Michael Madeja and Peter Århem
Molecular Pharmacology June 2003, 63 (6) 1417-1429; DOI: https://doi.org/10.1124/mol.63.6.1417
Johanna Nilsson
The Nobel Institute for Neurophysiology, Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden (J.N., P.Å.); and Institut für Physiologie, Münster, Germany (M.M.).
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Michael Madeja
The Nobel Institute for Neurophysiology, Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden (J.N., P.Å.); and Institut für Physiologie, Münster, Germany (M.M.).
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Peter Århem
The Nobel Institute for Neurophysiology, Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden (J.N., P.Å.); and Institut für Physiologie, Münster, Germany (M.M.).
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Abstract

To gain insights in the molecular mechanisms of anesthesia, we analyzed the effects of bupivacaine on a series of voltage-gated K+ channels (Kv1.1, -1.2, -1.5, -2.1, -3.1, and -3.2) and various mutant channels derived from Kv2.1, using Xenopus laevis oocytes. Two phenomenologically different blocking effects were seen at room temperature: a time-dependent block of Kv1 and Kv3 channels (Kd between 110 and 240 μM), and a time-independent block on Kv2.1 (Kd = 220 μM). At 32°C, however, Kv2.1 also showed a time-dependent block. Swapping the S6 helix between Kv1.2 and Kv2.1 introduced Kv1.2 features in Kv2.1. Critical residues were located in the N-terminal end of S6, positions 395 and 398. The triple substitution of residues 372, 373, and 374 in the S5-S6 linker decreased the bupivacaine affinity by 5-fold (Kd increased from 220 to 1170 μM). The results suggest that bupivacaine blocks Kv channels by an open-state–dependent mechanism and that Kv2.1 deviates from the other channels in allowing a partial closure of the channel with bupivacaine bound. The results also suggest that the binding site is located in the internal vestibule and that residues in the descending P-loop and the upper part of S6 are critical for the binding, most likely by allosteric mechanisms. A simple mechanistic scenario that explains the observations is presented. Thermodynamic considerations suggest that the interaction between bupivacaine and the channels is hydrophobic.

  • Received July 18, 2002.
  • Accepted March 10, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 63 (6)
Molecular Pharmacology
Vol. 63, Issue 6
1 Jun 2003
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Research ArticleArticle

Local Anesthetic Block of Kv Channels: Role of the S6 Helix and the S5-S6 Linker for Bupivacaine Action

Johanna Nilsson, Michael Madeja and Peter Århem
Molecular Pharmacology June 1, 2003, 63 (6) 1417-1429; DOI: https://doi.org/10.1124/mol.63.6.1417

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Research ArticleArticle

Local Anesthetic Block of Kv Channels: Role of the S6 Helix and the S5-S6 Linker for Bupivacaine Action

Johanna Nilsson, Michael Madeja and Peter Århem
Molecular Pharmacology June 1, 2003, 63 (6) 1417-1429; DOI: https://doi.org/10.1124/mol.63.6.1417
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