title: Kv3.3 Channels Bind Hax-1 and Arp2/3 to Assemble a Stable Local Actin Network that Regulates Channel Gating.
abstract: Mutations in the Kv3.3 potassium channel (KCNC3) cause cerebellar neurodegeneration and impair auditory processing. The cytoplasmic C terminus of Kv3.3 contains a proline-rich domain conserved in proteins that activate actin nucleation through Arp2/3. We found that Kv3.3 recruits Arp2/3 to the plasma membrane, resulting in formation of a relatively stable cortical actin filament network resistant to cytochalasin D that inhibits fast barbed end actin assembly. These Kv3.3-associated actin structures are required to prevent very rapid N-type channel inactivation during short depolarizations of the plasma membrane. The effects of Kv3.3 on the actin cytoskeleton are mediated by the binding of the cytoplasmic C terminus of Kv3.3 to Hax-1, an anti-apoptotic protein that regulates actin nucleation through Arp2/3. A human Kv3.3 mutation within a conserved proline-rich domain produces channels that bind Hax-1 but are impaired in recruiting Arp2/3 to the plasma membrane, resulting in growth cones with deficient actin veils in stem cell-derived neurons.
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520.
authors.forename: Yalan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520.
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Fleming
authors.affiliation: Department of Child Study Center and Neurobiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520.
authors.forename: Anahita
authors.initials: A
authors.lastname: Amiri
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520.
authors.forename: Lynda
authors.initials: L
authors.lastname: El-Hassar
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520.
authors.forename: Alexei A
authors.initials: AA
authors.lastname: Surguchev
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520.
authors.forename: Callen
authors.initials: C
authors.lastname: Hyland
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520.
authors.forename: David P
authors.initials: DP
authors.lastname: Jenkins
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520.
authors.forename: Rooma
authors.initials: R
authors.lastname: Desai
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520.
authors.forename: Maile R
authors.initials: MR
authors.lastname: Brown
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520.
authors.forename: Valeswara-Rao
authors.initials: VR
authors.lastname: Gazula
authors.affiliation: Department of Neurology, University of Florida College of Medicine, HSC Box 100236, Gainesville, FL 32610-0236.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Waters
authors.affiliation: Autifony Therapeutics Limited, Imperial College Incubator, Level 1 Bessemer Building, London, SW7 2AZ UK.
authors.forename: Charles H
authors.initials: CH
authors.lastname: Large
authors.affiliation: Department of Comparative Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520.
authors.forename: Tamas L
authors.initials: TL
authors.lastname: Horvath
authors.affiliation: Department of Neurology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520.
authors.forename: Dhasakumar
authors.initials: D
authors.lastname: Navaratnam
authors.affiliation: Department of Child Study Center and Neurobiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520.
authors.forename: Flora M
authors.initials: FM
authors.lastname: Vaccarino
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520.
authors.forename: Paul
authors.initials: P
authors.lastname: Forscher
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520.|Department of Cellular and Molecular Physiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520.
authors.forename: Leonard K
authors.initials: LK
authors.lastname: Kaczmarek
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism*; D051377:Actin-Related Protein 2 / Q000378:metabolism*; D051376:Actin-Related Protein 2-3 Complex / Q000378:metabolism; D051378:Actin-Related Protein 3 / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000595:Amino Acid Sequence; D002462:Cell Membrane / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000378:metabolism; D051670:Shaw Potassium Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D020754:Spinocerebellar Ataxias / Q000378:metabolism*; D020744:rac GTP-Binding Proteins / Q000378:metabolism
chemical_list: C495926:ACTR2 protein, human; C495928:ACTR3 protein, human; D051377:Actin-Related Protein 2; D051376:Actin-Related Protein 2-3 Complex; D051378:Actin-Related Protein 3; D048868:Adaptor Proteins, Signal Transducing; C104759:HAX1 protein, human; C489594:KCNC3 protein, human; D051670:Shaw Potassium Channels; D020744:rac GTP-Binding Proteins