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Cell. 2016 Apr 7;165(2):434-48. doi: 10.1016/j.cell.2016.02.009. Epub 2016 Mar 17.

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

Author information

1
Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
2
Department of Molecular, Cellular and Developmental Biology, Yale University, 219 Prospect Street, New Haven, CT 06520, USA.
3
Child Study Center and Department of Neurobiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
4
Department of Neurology, University of Florida College of Medicine, HSC Box 100236, Gainesville, FL 32610-0236, USA.
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, USA.
7
Department of Neurology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
8
Department of Molecular, Cellular and Developmental Biology, Yale University, 219 Prospect Street, New Haven, CT 06520, USA. Electronic address: paul.forscher@yale.edu.
9
Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA; Department of Cellular and Molecular Physiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA. Electronic address: leonard.kaczmarek@yale.edu.

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.

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PMID:
26997484
PMCID:
PMC4826296
DOI:
10.1016/j.cell.2016.02.009
[Indexed for MEDLINE]
Free PMC Article
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