RT Journal Article SR Electronic T1 The Neuroprotective Agent Riluzole Activates the Two P Domain K+ Channels TREK-1 and TRAAK JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 906 OP 912 VO 57 IS 5 A1 Duprat, Fabrice A1 Lesage, Florian A1 Patel, Amanda J. A1 Fink, Michel A1 Romey, Georges A1 Lazdunski, Michel YR 2000 UL http://molpharm.aspetjournals.org/content/57/5/906.abstract AB 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. The American Society for Pharmacology and Experimental Therapeutics