Selective positive modulator of calcium-activated potassium channels exerts beneficial effects in a mouse model of spinocerebellar ataxia type 2

Adebimpe W. Kasumu, Charlotte Hougaard, Frederik Rode, Thomas A. Jacobsen, Jean Marc Sabatier, Birgitte L. Eriksen, Dorte Strobæk, Xia Liang, Polina Egorova, Dasha Vorontsova, Palle Christophersen, Lars Christian B Ronn, Ilya Bezprozvanny

Research output: Contribution to journalArticle

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Abstract

Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disorder caused by a polyglutamine expansion within the Ataxin-2 (Atxn2) protein. Purkinje cells (PC) of the cerebellum fire irregularly and eventually die in SCA2. We show here that the type 2 small conductance calcium-activated potassium channel (SK2) play a key role in control of normal PC activity. Using cerebellar slices from transgenic SCA2 mice we demonstrate that SK channel modulators restore regular pacemaker activity of SCA2 PCs. Furthermore, we also show that oral delivery of a more selective positive modulator of SK2/3 channels (NS13001) alleviates behavioral and neuropathological phenotypes of aging SCA2 transgenic mice. We conclude that SK2 channels constitute a therapeutic target for SCA2 treatment and that the developed selective SK2/3 modulator NS13001 holds promise as a potential therapeutic agent for treatment of SCA2 and possibly other cerebellar ataxias.

Original languageEnglish (US)
Pages (from-to)1340-1353
Number of pages14
JournalChemistry and Biology
Volume19
Issue number10
DOIs
StatePublished - Oct 26 2012

Fingerprint

Spinocerebellar Ataxias
Calcium-Activated Potassium Channels
Modulators
Small-Conductance Calcium-Activated Potassium Channels
Pacemakers
Purkinje Cells
Fires
Aging of materials
Cerebellar Ataxia
Neurodegenerative Diseases
Cerebellum
Transgenic Mice
4-(chlorophenyl)-(2-(3,5-dimethylpyrazol-1-yl)-9-methyl-9H-purin-6-yl)amine
Phenotype
Therapeutics

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Molecular Biology
  • Clinical Biochemistry
  • Molecular Medicine
  • Pharmacology

Cite this

Selective positive modulator of calcium-activated potassium channels exerts beneficial effects in a mouse model of spinocerebellar ataxia type 2. / Kasumu, Adebimpe W.; Hougaard, Charlotte; Rode, Frederik; Jacobsen, Thomas A.; Sabatier, Jean Marc; Eriksen, Birgitte L.; Strobæk, Dorte; Liang, Xia; Egorova, Polina; Vorontsova, Dasha; Christophersen, Palle; Ronn, Lars Christian B; Bezprozvanny, Ilya.

In: Chemistry and Biology, Vol. 19, No. 10, 26.10.2012, p. 1340-1353.

Research output: Contribution to journalArticle

Kasumu, AW, Hougaard, C, Rode, F, Jacobsen, TA, Sabatier, JM, Eriksen, BL, Strobæk, D, Liang, X, Egorova, P, Vorontsova, D, Christophersen, P, Ronn, LCB & Bezprozvanny, I 2012, 'Selective positive modulator of calcium-activated potassium channels exerts beneficial effects in a mouse model of spinocerebellar ataxia type 2', Chemistry and Biology, vol. 19, no. 10, pp. 1340-1353. https://doi.org/10.1016/j.chembiol.2012.07.013
Kasumu, Adebimpe W. ; Hougaard, Charlotte ; Rode, Frederik ; Jacobsen, Thomas A. ; Sabatier, Jean Marc ; Eriksen, Birgitte L. ; Strobæk, Dorte ; Liang, Xia ; Egorova, Polina ; Vorontsova, Dasha ; Christophersen, Palle ; Ronn, Lars Christian B ; Bezprozvanny, Ilya. / Selective positive modulator of calcium-activated potassium channels exerts beneficial effects in a mouse model of spinocerebellar ataxia type 2. In: Chemistry and Biology. 2012 ; Vol. 19, No. 10. pp. 1340-1353.
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