Kv3.3 Channels Bind Hax-1 and Arp2/3 to Assemble a Stable Local Actin Network that Regulates Channel Gating
Document Type
Article
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.
Medical Subject Headings
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, genetics, metabolism); Signal Transduction; Spinocerebellar Ataxias (metabolism); rac GTP-Binding Proteins (metabolism)
Publication Date
4-7-2016
Publication Title
Cell
E-ISSN
1097-4172
Volume
165
Issue
2
First Page
434
Last Page
448
PubMed ID
26997484
Digital Object Identifier (DOI)
10.1016/j.cell.2016.02.009
Recommended Citation
Zhang, Yalan; Zhang, Xiao-Feng; Fleming, Matthew R.; Amiri, Anahita; El-Hassar, Lynda; Surguchev, Alexei A.; Hyland, Callen; Jenkins, David P.; Desai, Rooma; Brown, Maile R.; Gazula, Valeswara-Rao; Waters, Michael F.; Large, Charles H.; Horvath, Tamas L.; Navaratnam, Dhasakumar; Vaccarino, Flora M.; Forscher, Paul; and Kaczmarek, Leonard K., "Kv3.3 Channels Bind Hax-1 and Arp2/3 to Assemble a Stable Local Actin Network that Regulates Channel Gating" (2016). Translational Neuroscience. 1354.
https://scholar.barrowneuro.org/neurobiology/1354