Spinocerebellar ataxia type 19/22 mutations alter heterocomplex Kv4.3 channel function and gating in a dominant manner

Anna Duarri Pique, Meng-Chin A. Lin, Michiel R. Fokkens, Michel Meijer, Cleo J. L. M. Smeets, Esther A. R. Nibbeling, Erik Boddeke, Richard J. Sinke, Harm H. Kampinga, Diane M. Papazian, Dineke S. Verbeek*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

The dominantly inherited cerebellar ataxias are a heterogeneous group of neurodegenerative disorders caused by Purkinje cell loss in the cerebellum. Recently, we identified loss-of-function mutations in the KCND3 gene as the cause of spinocerebellar ataxia type 19/22 (SCA19/22), revealing a previously unknown role for the voltage-gated potassium channel, Kv4.3, in Purkinje cell survival. However, how mutant Kv4.3 affects wild-type Kv4.3 channel functioning remains unknown. We provide evidence that SCA19/22-mutant Kv4.3 exerts a dominant negative effect on the trafficking and surface expression of wild-type Kv4.3 in the absence of its regulatory subunit, KChIP2. Notably, this dominant negative effect can be rescued by the presence of KChIP2. We also found that all SCA19/22-mutant subunits either suppress wild-type Kv4.3 current amplitude or alter channel gating in a dominant manner. Our findings suggest that altered Kv4.3 channel localization and/or functioning resulting from SCA19/22 mutations may lead to Purkinje cell loss, neurodegeneration and ataxia.

Original languageEnglish
Pages (from-to)3387-3399
Number of pages13
JournalCellular and molecular life sciences
Volume72
Issue number17
DOIs
Publication statusPublished - Sep-2015

Keywords

  • KCND3
  • Kv4.3
  • Spinocerebellar ataxia
  • Purkinje cells
  • Voltage-gated potassium channel
  • TRANSMEMBRANE CONDUCTANCE REGULATOR
  • POTASSIUM CHANNEL
  • K+ CHANNEL
  • BIOPHYSICAL PROPERTIES
  • LOW-TEMPERATURE
  • EXPRESSION
  • TRANSIENT
  • CURRENTS
  • BRAIN
  • RAT

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