title: Elimination of fast inactivation in Kv4 A-type potassium channels by an auxiliary subunit domain.
abstract: The Kv4 A-type potassium currents contribute to controlling the frequency of slow repetitive firing and back-propagation of action potentials in neurons and shape the action potential in heart. Kv4 currents exhibit rapid activation and inactivation and are specifically modulated by K-channel interacting proteins (KChIPs). Here we report the discovery and functional characterization of a modular K-channel inactivation suppressor (KIS) domain located in the first 34 aa of an additional KChIP (KChIP4a). Coexpression of KChIP4a with Kv4 alpha-subunits abolishes fast inactivation of the Kv4 currents in various cell types, including cerebellar granule neurons. Kinetic analysis shows that the KIS domain delays Kv4.3 opening, but once the channel is open, it disrupts rapid inactivation and slows Kv4.3 closing. Accordingly, KChIP4a increases the open probability of single Kv4.3 channels. The net effects of KChIP4a and KChIP1-3 on Kv4 gating are quite different. When both KChIP4a and KChIP1 are present, the Kv4.3 current shows mixed inactivation profiles dependent on KChIP4a/KChIP1 ratios. The KIS domain effectively converts the A-type Kv4 current to a slowly inactivating delayed rectifier-type potassium current. This conversion is opposite to that mediated by the Kv1-specific "ball" domain of the Kv beta 1 subunit. Together, these results demonstrate that specific auxiliary subunits with distinct functions actively modulate gating of potassium channels that govern membrane excitability.
authors.affiliation: Millennium Pharmaceuticals, Inc., 75 Sidney Street, Cambridge, MA 02139, USA.
authors.forename: Mats H
authors.initials: MH
authors.lastname: Holmqvist
authors.forename: Jie
authors.initials: J
authors.lastname: Cao
authors.forename: Ricardo
authors.initials: R
authors.lastname: Hernandez-Pineda
authors.forename: Michael D
authors.initials: MD
authors.lastname: Jacobson
authors.forename: Karen I
authors.initials: KI
authors.lastname: Carroll
authors.forename: M Amy
authors.initials: MA
authors.lastname: Sung
authors.forename: Maria
authors.initials: M
authors.lastname: Betty
authors.forename: Pei
authors.initials: P
authors.lastname: Ge
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Gilbride
authors.forename: Melissa E
authors.initials: ME
authors.lastname: Brown
authors.forename: Mark E
authors.initials: ME
authors.lastname: Jurman
authors.forename: Deborah
authors.initials: D
authors.lastname: Lawson
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Silos-Santiago
authors.forename: Yu
authors.initials: Y
authors.lastname: Xie
authors.forename: Manuel
authors.initials: M
authors.lastname: Covarrubias
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Rhodes
authors.forename: Peter S
authors.initials: PS
authors.lastname: Distefano
authors.forename: W Frank
authors.initials: WF
authors.lastname: An
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D066298:In Vitro Techniques; D015640:Ion Channel Gating; D007700:Kinetics; D051605:Kv Channel-Interacting Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009865:Oocytes / Q000378:metabolism; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated; D017434:Protein Structure, Tertiary; D021122:Protein Subunits; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D051672:Shal Potassium Channels; D014981:Xenopus
chemical_list: D002135:Calcium-Binding Proteins; C496753:KCNIP4 protein, human; C497022:Kcnd3 protein, mouse; C496754:Kcnip1 protein, mouse; C452817:Kcnip4 protein, rat; D051605:Kv Channel-Interacting Proteins; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D021122:Protein Subunits; D011994:Recombinant Proteins; D051672:Shal Potassium Channels