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 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.
Duprat
F
F
Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Valbonne, France.
Lesage
F
F
Patel
A J
AJ
Fink
M
M
Romey
G
G
Lazdunski
M
M
D000818:Animals; D019556:COS Cells; D000242:Cyclic AMP / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D015221:Potassium Channels / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D024683:Potassium Channels, Tandem Pore Domain; D017434:Protein Structure, Tertiary / Q000187:drug effects; D019782:Riluzole / Q000494:pharmacology*; D014162:Transfection
D018696:Neuroprotective Agents; D015221:Potassium Channels; D024683:Potassium Channels, Tandem Pore Domain; C103742:potassium channel protein TREK-1; D019782:Riluzole; D000242:Cyclic AMP