title: The neuroprotective agent sipatrigine (BW619C89) potently inhibits the human tandem pore-domain K(+) channels TREK-1 and TRAAK.
abstract: 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 resting membrane potential. Quantitative mRNA expression analysis using Taqman 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 arachidonic acid. The neuroprotective agent sipatrigine (10 microM) inhibited both hTREK-1 (73.3+/-4.4%) and hTRAAK (45.1+/-11.2%) in a reversible, voltage-independent manner. Inhibition of both channels was dose-dependent and for TREK-1 occurred with an IC(50) of 4 microM. The related compound lamotrigine, which is a better anticonvulsant but weaker neuroprotective agent than sipatrigine, was a far less effective antagonist of both channels, producing <10% inhibition at a concentration of 10 microM.
authors.affiliation: Neuroscience Research, SmithKline Beecham Pharmaceuticals, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK. helen_j_meadows@sbphrd.com
authors.forename: H J
authors.initials: HJ
authors.lastname: Meadows
authors.forename: C G
authors.initials: CG
authors.lastname: Chapman
authors.forename: D M
authors.initials: DM
authors.lastname: Duckworth
authors.forename: R E
authors.initials: RE
authors.lastname: Kelsell
authors.forename: P R
authors.initials: PR
authors.lastname: Murdock
authors.forename: S
authors.initials: S
authors.lastname: Nasir
authors.forename: G
authors.initials: G
authors.lastname: Rennie
authors.forename: A D
authors.initials: AD
authors.lastname: Randall
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000502:physiology*; D002460:Cell Line; D005260:Female; D006801:Humans; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology*; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D024683:Potassium Channels, Tandem Pore Domain; D011743:Pyrimidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D014162:Transfection; D014982:Xenopus laevis
chemical_list: C503432:KCNK4 protein, human; C503433:Kcnk4 protein, mouse; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D010879:Piperazines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024683:Potassium Channels, Tandem Pore Domain; D011743:Pyrimidines; D012333:RNA, Messenger; C103742:potassium channel protein TREK-1; C081980:sipatrigine