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

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.
Yalan Zhang # 1,  Xiao-Feng Zhang # 2,  Matthew R Fleming 1,  Anahita Amiri 3,  Lynda El-Hassar 1,  Alexei A Surguchev 1,  Callen Hyland 2,  David P Jenkins 1,  Rooma Desai 1,  Maile R Brown 1,  Valeswara-Rao Gazula 1,  Michael F Waters 4,  Charles H Large 5,  Tamas L Horvath 6,  Dhasakumar Navaratnam 7,  Flora M Vaccarino 3,  Paul Forscher 2,  Leonard K Kaczmarek 1 8
Affiliations

Affiliations

  • 1 Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520.
  • 2 Department of Molecular, Cellular and Developmental Biology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520.
  • 3 Department of Child Study Center and Neurobiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520.
  • 4 Department of Neurology, University of Florida College of Medicine, HSC Box 100236, Gainesville, FL 32610-0236.
  • 5 Autifony Therapeutics Limited, Imperial College Incubator, Level 1 Bessemer Building, London, SW7 2AZ UK.
  • 6 Department of Comparative Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520.
  • 7 Department of Neurology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520.
  • 8 Department of Cellular and Molecular Physiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520.
  • # Contributed equally.
PMID: 26997484 DOI: 10.1016/j.cell.2016.02.009
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.

Figures