title: The epilepsy-linked Lgi1 protein assembles into presynaptic Kv1 channels and inhibits inactivation by Kvbeta1.
abstract: The voltage-gated potassium (Kv) channel subunit Kv1.1 is a major constituent of presynaptic A-type channels that modulate synaptic transmission in CNS neurons. Here, we show that Kv1.1-containing channels are complexed with Lgi1, the functionally unassigned product of the leucine-rich glioma inactivated gene 1 (LGI1), which is causative for an autosomal dominant form of lateral temporal lobe epilepsy (ADLTE). In the hippocampal formation, both Kv1.1 and Lgi1 are coassembled with Kv1.4 and Kvbeta1 in axonal terminals. In A-type channels composed of these subunits, Lgi1 selectively prevents N-type inactivation mediated by the Kvbeta1 subunit. In contrast, defective Lgi1 molecules identified in ADLTE patients fail to exert this effect resulting in channels with rapid inactivation kinetics. The results establish Lgi1 as a novel subunit of Kv1.1-associated protein complexes and suggest that changes in inactivation gating of presynaptic A-type channels may promote epileptic activity.
authors.affiliation: Logopharm GmbH, Hermann-Herder-Str. 7, 79104 Freiburg, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Schulte
authors.forename: Jörg-Oliver
authors.initials: JO
authors.lastname: Thumfart
authors.forename: Nikolaj
authors.initials: N
authors.lastname: Klöcker
authors.forename: Claudia A
authors.initials: CA
authors.lastname: Sailer
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Bildl
authors.forename: Martin
authors.initials: M
authors.lastname: Biniossek
authors.forename: Doris
authors.initials: D
authors.lastname: Dehn
authors.forename: Thomas
authors.initials: T
authors.lastname: Deller
authors.forename: Silke
authors.initials: S
authors.lastname: Eble
authors.forename: Karen
authors.initials: K
authors.lastname: Abbass
authors.forename: Tanja
authors.initials: T
authors.lastname: Wangler
authors.forename: Hans-Günther
authors.initials: HG
authors.lastname: Knaus
authors.forename: Bernd
authors.initials: B
authors.lastname: Fakler
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D001923:Brain Chemistry; D002462:Cell Membrane / Q000378:metabolism; D004307:Dose-Response Relationship, Radiation; D004558:Electric Stimulation / Q000379:methods; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D047908:Intracellular Signaling Peptides and Proteins; D051662:Kv1.1 Potassium Channel / Q000502:physiology*; D051663:Kv1.2 Potassium Channel / Q000502:physiology*; D013058:Mass Spectrometry / Q000379:methods; D008564:Membrane Potentials / Q000502:physiology; D016296:Mutagenesis / Q000502:physiology; D009154:Mutation; D009433:Neural Inhibition / Q000502:physiology*; D009865:Oocytes; D018408:Patch-Clamp Techniques / Q000379:methods; D011487:Protein Conformation; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D016415:Sequence Alignment; D016622:Silver Staining / Q000379:methods; D014162:Transfection / Q000379:methods; D014981:Xenopus
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D051663:Kv1.2 Potassium Channel; C116499:LGI1 protein, human; D011506:Proteins; D051662:Kv1.1 Potassium Channel