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
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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
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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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