The neuroprotective agent sipatrigine (BW619C89) potently inhibits the human tandem pore-domain K+ channels TREK-1 and TRAAK

We have cloned and functionally expressed the human orthologue of the mouse TRAAK gene. When cDNA for hTRAAK is expressed in either Xenopus oocytes or HEK293 cells it forms a K+-selective conductance and hyperpolarises the re sting membrane potential. Quantitative mRNA expression analysis using Taqma n revealed that hTRAAK mRNA is predominantly present in the central nervous system where it exhibits a regionally diverse pattern of expression. Like the related channel TREK-1, the activity of TRAAK was potentiated by arachi donic acid. The neuroprotective agent sipatrigine (10 muM) inhibited both h TREK-1 (73.3+/-3.4%) and hTRAAK (45.1+/-11.2%) in a reversible, voltage-ind ependent manner. inhibition of both channels was dose-dependent and for TRE K-I occurred with an IC50 of 4 muM. The related compound lamotrigine, which is a better anticonvulsant but weaker neuroprotective agent than sipatrigi ne, was a far less effective antagonist of both channels, producing <10% in hibition at a concentration of 10 <mu>M. (C) 2001 Elsevier Science B.V. All rights reserved.