The neuroprotective agent riluzole activates the two P domain K(+) channels TREK-1 and TRAAK

• Published in: Molecular pharmacology Vol. 57; no. 5; p. 906
• Main Authors: Duprat, F, Lesage, F, Patel, A J, Fink, M, Romey, G, Lazdunski, M
• Format: Journal Article
• Language: English
• Published: United States 01-05-2000
• Subjects: Animals; COS Cells; Cyclic AMP - metabolism; Neuroprotective Agents - pharmacology; Potassium Channels - chemistry; Potassium Channels - drug effects; Potassium Channels - metabolism; Potassium Channels, Tandem Pore Domain; Protein Structure, Tertiary - drug effects; Riluzole - pharmacology; Transfection
• ISSN: 0026-895X

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.