Referenced in: none

Automatically associated channels: KChIP2 , Kv1.4 , Kv3.1 , Kv4.3

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

Authors: Anna Duarri, 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

Journal, date & volume: Cell. Mol. Life Sci., 2015 Sep , 72, 3387-99

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/25854634

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.