caa a22 4500 606176292 CHVBK 20210128100746.0 cr unu---uuuuu 210128e20150901xx s 000 0 eng 10.1007/s00018-015-1894-2 doi (NATIONALLICENCE)springer-10.1007/s00018-015-1894-2 Spinocerebellar ataxia type 19/22 mutations alter heterocomplex Kv4.3 channel function and gating in a dominant manner [Elektronische Daten] [Anna Duarri, Meng-Chin Lin, Michiel Fokkens, Michel Meijer, Cleo Smeets, Esther Nibbeling, Erik Boddeke, Richard Sinke, Harm Kampinga, Diane Papazian, Dineke Verbeek] 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. The Author(s), 2015 KCND3 nationallicence Kv4.3 nationallicence Spinocerebellar ataxia nationallicence Purkinje cells nationallicence Voltage-gated potassium channel nationallicence Duarri Anna Department of Genetics, University of Groningen, University Medical Center Groningen, PO Box 30 001, 9700 RB, Groningen, The Netherlands aut Lin Meng-Chin Department of Physiology, University of California at Los Angeles, 90095-1751, Los Angeles, CA, USA aut Fokkens Michiel Department of Genetics, University of Groningen, University Medical Center Groningen, PO Box 30 001, 9700 RB, Groningen, The Netherlands aut Meijer Michel Department of Medical Physiology, University of Groningen, University Medical Center Groningen, 9700 RB, Groningen, The Netherlands aut Smeets Cleo Department of Genetics, University of Groningen, University Medical Center Groningen, PO Box 30 001, 9700 RB, Groningen, The Netherlands aut Nibbeling Esther Department of Genetics, University of Groningen, University Medical Center Groningen, PO Box 30 001, 9700 RB, Groningen, The Netherlands aut Boddeke Erik Department of Medical Physiology, University of Groningen, University Medical Center Groningen, 9700 RB, Groningen, The Netherlands aut Sinke Richard Department of Genetics, University of Groningen, University Medical Center Groningen, PO Box 30 001, 9700 RB, Groningen, The Netherlands aut Kampinga Harm Department of Cell Biology, University of Groningen, University Medical Center Groningen, 9700 RB, Groningen, The Netherlands aut Papazian Diane Department of Physiology, University of California at Los Angeles, 90095-1751, Los Angeles, CA, USA aut Verbeek Dineke Department of Genetics, University of Groningen, University Medical Center Groningen, PO Box 30 001, 9700 RB, Groningen, The Netherlands aut Cellular and Molecular Life Sciences Springer Basel 72/17(2015-09-01), 3387-3399 1420-682X 72:17<3387 2015 72 18 https://doi.org/10.1007/s00018-015-1894-2 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00018-015-1894-2 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Duarri Anna Department of Genetics, University of Groningen, University Medical Center Groningen, PO Box 30 001, 9700 RB, Groningen, The Netherlands aut NATIONALLICENCE 700 1- Lin Meng-Chin Department of Physiology, University of California at Los Angeles, 90095-1751, Los Angeles, CA, USA aut NATIONALLICENCE 700 1- Fokkens Michiel Department of Genetics, University of Groningen, University Medical Center Groningen, PO Box 30 001, 9700 RB, Groningen, The Netherlands aut NATIONALLICENCE 700 1- Meijer Michel Department of Medical Physiology, University of Groningen, University Medical Center Groningen, 9700 RB, Groningen, The Netherlands aut NATIONALLICENCE 700 1- Smeets Cleo Department of Genetics, University of Groningen, University Medical Center Groningen, PO Box 30 001, 9700 RB, Groningen, The Netherlands aut NATIONALLICENCE 700 1- Nibbeling Esther Department of Genetics, University of Groningen, University Medical Center Groningen, PO Box 30 001, 9700 RB, Groningen, The Netherlands aut NATIONALLICENCE 700 1- Boddeke Erik Department of Medical Physiology, University of Groningen, University Medical Center Groningen, 9700 RB, Groningen, The Netherlands aut NATIONALLICENCE 700 1- Sinke Richard Department of Genetics, University of Groningen, University Medical Center Groningen, PO Box 30 001, 9700 RB, Groningen, The Netherlands aut NATIONALLICENCE 700 1- Kampinga Harm Department of Cell Biology, University of Groningen, University Medical Center Groningen, 9700 RB, Groningen, The Netherlands aut NATIONALLICENCE 700 1- Papazian Diane Department of Physiology, University of California at Los Angeles, 90095-1751, Los Angeles, CA, USA aut NATIONALLICENCE 700 1- Verbeek Dineke Department of Genetics, University of Groningen, University Medical Center Groningen, PO Box 30 001, 9700 RB, Groningen, The Netherlands aut NATIONALLICENCE 773 0- Cellular and Molecular Life Sciences Springer Basel 72/17(2015-09-01), 3387-3399 1420-682X 72:17<3387 2015 72 18