Kv3.3 Channels Bind Hax-1 and Arp2/3 to Assemble a Stable Local Actin Network that Regulates Channel Gating

Cell. 2016 Apr 7;165(2):434-448. doi: 10.1016/j.cell.2016.02.009. Epub 2016 Mar 17.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actin Cytoskeleton / metabolism*
  • Actin-Related Protein 2 / metabolism*
  • Actin-Related Protein 2-3 Complex / metabolism
  • Actin-Related Protein 3 / metabolism*
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Amino Acid Sequence
  • Cell Membrane / metabolism
  • Molecular Sequence Data
  • Mutation
  • Neurons / metabolism
  • Pluripotent Stem Cells / metabolism
  • Shaw Potassium Channels / chemistry
  • Shaw Potassium Channels / genetics
  • Shaw Potassium Channels / metabolism*
  • Signal Transduction
  • Spinocerebellar Ataxias / metabolism*
  • rac GTP-Binding Proteins / metabolism

Substances

  • ACTR2 protein, human
  • ACTR3 protein, human
  • Actin-Related Protein 2
  • Actin-Related Protein 2-3 Complex
  • Actin-Related Protein 3
  • Adaptor Proteins, Signal Transducing
  • HAX1 protein, human
  • KCNC3 protein, human
  • Shaw Potassium Channels
  • rac GTP-Binding Proteins