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Molecular Pharmacology

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Research ArticleArticle

The Neuroprotective Agent Riluzole Activates the Two P Domain K+ Channels TREK-1 and TRAAK

Fabrice Duprat, Florian Lesage, Amanda J. Patel, Michel Fink, Georges Romey and Michel Lazdunski
Molecular Pharmacology May 2000, 57 (5) 906-912;
Fabrice Duprat
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Florian Lesage
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Amanda J. Patel
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Michel Fink
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Georges Romey
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Michel Lazdunski
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Abstract

Riluzole (RP 54274) is a potent neuroprotective agent with anticonvulsant, sedative, and anti-ischemic properties. It is currently used in the treatment of amyotrophic lateral sclerosis. This article reports that riluzole is an activator of TREK-1 and TRAAK, two important members of a new structural family of mammalian background K+ channels with four transmembrane domains and two pore regions. Whereas riluzole activation of TRAAK is sustained, activation of TREK-1 is transient and is followed by an inhibition. The inhibitory process is attributable to an increase of the intracellular cAMP concentration by riluzole that produces a protein kinase A-dependent inhibition of TREK-1. Mutants of TREK-1 lacking the Ser residue where the kinase A phosphorylation takes place are activated in a sustained manner by riluzole. TRAAK is permanently activated by riluzole because, unlike TREK-1, it lacks the negative regulation by cAMP.

Footnotes

  • Send reprint requests to: Prof. Michel Lazdunski, Institut de Pharmacologie Moléculaire et Cellulaire–Centre National de la Recherche Scientifique–UPR 411, 660 route des Lucioles, Sophia Antipolis, 06560 Valbonne, France. E-mail: ipmc{at}ipmc.cnrs.fr

  • 1 This work was supported by the Centre National de la Recherche Scientifique and the Association Française Contre les Myopathies.

  • Abbreviations:
    PDE
    phosphodiesterase
    PKA
    protein kinase A
    8CPT
    8-(4-chlorophenylthio)
    IBMX
    isobutyl methyl xanthine
    DNP
    dinitrophenol
    MCD
    mast cell degranulating
    • Received October 18, 1999.
    • Accepted January 6, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 57 (5)
Molecular Pharmacology
Vol. 57, Issue 5
1 May 2000
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Research ArticleArticle

The Neuroprotective Agent Riluzole Activates the Two P Domain K+ Channels TREK-1 and TRAAK

Fabrice Duprat, Florian Lesage, Amanda J. Patel, Michel Fink, Georges Romey and Michel Lazdunski
Molecular Pharmacology May 1, 2000, 57 (5) 906-912;

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Research ArticleArticle

The Neuroprotective Agent Riluzole Activates the Two P Domain K+ Channels TREK-1 and TRAAK

Fabrice Duprat, Florian Lesage, Amanda J. Patel, Michel Fink, Georges Romey and Michel Lazdunski
Molecular Pharmacology May 1, 2000, 57 (5) 906-912;
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