Publication

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

Duarri Pique, A., Lin, M-C. A., Fokkens, M. R., Meijer, M., Smeets, C. J. L. M., Nibbeling, E. A. R., Boddeke, E., Sinke, R. J., Kampinga, H. H., Papazian, D. M. & Verbeek, D. S., Sep-2015, In : Cellular and molecular life sciences. 72, 17, p. 3387-3399 13 p.

Research output: Contribution to journalArticleAcademicpeer-review

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
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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