The Enigmatic Drug Binding Site for Sodium Channel Inhibitors

A. Mike, Peter Lukacs

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Local anesthetics have been in clinical use since 1884, and different aspects of the local anesthetic binding site have been studied in enormous detail. In spite of all these efforts, some of the most fundamental questions - such as which exact residues constitute the binding site, how many binding sites exist, do local anesthetics share their binding site(s) with other sodium channel inhibitors, and what are the mechanisms of inhibition - are still largely unanswered. We review accumulated data on the "local anesthetic receptor" and discuss controversial points, such as possible mechanisms of inhibition, the possibility of additional binding sites, the orientation of S6 helices, and the internal vs. external position of the anticonvulsant binding site. We describe the four following specific groups of functionally important residues: i) conserved asparagines six residues below the hinge residues; we propose that they are oriented toward the external surface of S6 helices, and have a critical role in the coupling of voltage sensors to gating, ii) residues lining the inner vestibule and constructing the "orthodox" binding site, iii) residues around the outer vestibule, which have been proposed to constitute an alternative external binding site, and iv) residues determining external access for quaternary amine inhibitors, such as QX314. We conclude that sodium channel inhibitors must be heterogenous in terms of binding sites and inhibition mechanisms, and propose that this heterogeneity should be taken into consideration during drug development.

Original languageEnglish
Pages (from-to)129-144
Number of pages16
JournalCurrent Molecular Pharmacology
Volume3
Issue number3
Publication statusPublished - 2010

Fingerprint

Sodium Channel Blockers
Binding Sites
Pharmaceutical Preparations
Local Anesthetics
S 6
Asparagine
Anticonvulsants
Amines

Keywords

  • Antiarrhythmic
  • Anticonvulsant
  • Binding site
  • Blocker
  • Local anesthetic
  • Model
  • Mutagenesis
  • Sodium channel

ASJC Scopus subject areas

  • Drug Discovery
  • Pharmacology
  • Molecular Medicine

Cite this

The Enigmatic Drug Binding Site for Sodium Channel Inhibitors. / Mike, A.; Lukacs, Peter.

In: Current Molecular Pharmacology, Vol. 3, No. 3, 2010, p. 129-144.

Research output: Contribution to journalArticle

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