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

Riluzole (RP 54274) is a potent neuroprotective agent with anticonvulsant, sedative, and anti-ischemic properties. It is currently used in the treatme nt 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, a ctivation of TREK-1 is transient and is followed by an inhibition. The inhi bitory process is attributable to an increase of the intracellular cAMP con centration by riluzole that produces a protein kinase A-dependent inhibitio n of TREK-1. Mutants of TREK-1 lacking the Ser residue where the kinase A p hosphorylation takes place are activated in a sustained manner by riluzole. TRAAK is permanently activated by riluzole because, unlike TREK-1, it lack s the negative regulation by cAMP.