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 Strøbæk; Xia Liang; Polina Egorova; Dasha Vorontsova; Palle Christophersen; Lars Christian B Rønn; Ilya Bezprozvanny

doi:10.1016/j.chembiol.2012.07.013

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

Chem Biol. 2012 Oct 26;19(10):1340-53. doi: 10.1016/j.chembiol.2012.07.013.

Authors

Adebimpe W Kasumu¹, Charlotte Hougaard, Frederik Rode, Thomas A Jacobsen, Jean Marc Sabatier, Birgitte L Eriksen, Dorte Strøbæk, Xia Liang, Polina Egorova, Dasha Vorontsova, Palle Christophersen, Lars Christian B Rønn, Ilya Bezprozvanny

Affiliation

¹ Department of Physiology, UT Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adenine / analogs & derivatives*
Adenine / chemistry
Adenine / pharmacology
Adenine / therapeutic use
Animals
Calcium / metabolism
Cerebellum / cytology
Disease Models, Animal
HEK293 Cells
Humans
In Vitro Techniques
Mice
Mice, Inbred C57BL
Mice, Transgenic
Motor Activity / drug effects
Patch-Clamp Techniques
Purkinje Cells / drug effects*
Purkinje Cells / physiology
Pyrazoles / chemistry
Pyrazoles / pharmacology*
Pyrazoles / therapeutic use
Rats
Rats, Sprague-Dawley
Small-Conductance Calcium-Activated Potassium Channels / chemistry*
Small-Conductance Calcium-Activated Potassium Channels / metabolism
Spinocerebellar Ataxias / drug therapy
Spinocerebellar Ataxias / metabolism
Spinocerebellar Ataxias / pathology

Substances

4-(chlorophenyl)-(2-(3,5-dimethylpyrazol-1-yl)-9-methyl-9H-purin-6-yl)amine
Kcnn2 protein, mouse
Kcnn3 protein, mouse
Pyrazoles
Small-Conductance Calcium-Activated Potassium Channels
Adenine
Calcium

Abstract

Publication types

MeSH terms

Substances

Grants and funding