Title

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

Authors

Yalan Zhang, Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520.
Xiao-Feng Zhang, Department of Molecular, Cellular and Developmental Biology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520.
Matthew R. Fleming, Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520.
Anahita Amiri, Department of Child Study Center and Neurobiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520.
Lynda El-Hassar, Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520.
Alexei A. Surguchev, Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520.
Callen Hyland, Department of Molecular, Cellular and Developmental Biology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520.
David P. Jenkins, Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520.
Rooma Desai, Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520.
Maile R. Brown, Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520.
Valeswara-Rao Gazula, Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520.
Michael F. Waters, Department of Neurology, University of Florida College of Medicine, HSC Box 100236, Gainesville, FL 32610-0236.
Charles H. Large, Autifony Therapeutics Limited, Imperial College Incubator, Level 1 Bessemer Building, London, SW7 2AZ UK.
Tamas L. Horvath, Department of Comparative Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520.
Dhasakumar Navaratnam, Department of Neurology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520.
Flora M. Vaccarino, Department of Child Study Center and Neurobiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520.
Paul Forscher, Department of Molecular, Cellular and Developmental Biology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520.
Leonard K. Kaczmarek, Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520.

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

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