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KCa channels as therapeutic targets in episodic ataxia type-2.

ABSTRACT: Episodic ataxia type-2 (EA2) is an inherited movement disorder caused by mutations in the gene encoding the Ca(v)2.1alpha1 subunit of the P/Q-type voltage-gated calcium channel that result in an overall reduction in the P/Q-type calcium current. A consequence of these mutations is loss of precision of pacemaking in cerebellar Purkinje cells. This diminished precision reduces the information encoded by Purkinje cells and is thought to contribute to symptoms associated with this disorder. The loss of the precision of pacemaking in EA2 is the consequence of reduced activation of calcium-dependent potassium channels (K(Ca)) by the smaller calcium current and in vitro can be pharmacologically restored by K(Ca) activators. We used a well established mouse model of EA2, the tottering (tg/tg) mouse, to examine the potential therapeutic utility of one such Food and Drug Administration (FDA)-approved compound, chlorzoxazone (CHZ). Compared with wild-type Purkinje cells, we found the firing rate of tg/tg Purkinje cells in acutely prepared cerebellar slices to be very irregular. Bath application of CHZ successfully restored the precision of pacemaking in a dose-dependent manner. Oral administration of CHZ to tg/tg mice improved their baseline motor performance and reduced the severity, frequency, and duration of episodes of dyskinesia without producing any adverse effects. We propose the use of CHZ, which is currently FDA approved as a muscle relaxant, as a safe and novel treatment of EA2.

SUBMITTER: Alvina K

PROVIDER: S-EPMC2909841 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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KCa channels as therapeutic targets in episodic ataxia type-2.

Alviña Karina K Khodakhah Kamran K

The Journal of neuroscience : the official journal of the Society for Neuroscience 20100501 21

Episodic ataxia type-2 (EA2) is an inherited movement disorder caused by mutations in the gene encoding the Ca(v)2.1alpha1 subunit of the P/Q-type voltage-gated calcium channel that result in an overall reduction in the P/Q-type calcium current. A consequence of these mutations is loss of precision of pacemaking in cerebellar Purkinje cells. This diminished precision reduces the information encoded by Purkinje cells and is thought to contribute to symptoms associated with this disorder. The loss ...[more]

PMID: 20505091

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Project description:Voltage-gated CaV2.1 channels comprise a pore-forming α1A subunit with auxiliary α2δ and β subunits. CaV2.1 channels play an essential role in regulating synaptic signaling. Mutations in the human gene encoding the CaV2.1 subunit are associated with the cerebellar disease episodic ataxia type 2 (EA2). Several EA2-causing mutants exhibit impaired protein stability and exert dominant-negative suppression of CaV2.1 wild-type (WT) protein expression via aberrant proteasomal degradation. Here, we set out to delineate the protein degradation mechanism of human CaV2.1 subunit by identifying RNF138, an E3 ubiquitin ligase, as a novel CaV2.1-binding partner. In neurons, RNF138 and CaV2.1 coexist in the same protein complex and display notable subcellular colocalization at presynaptic and postsynaptic regions. Overexpression of RNF138 promotes polyubiquitination and accelerates protein turnover of CaV2.1. Disrupting endogenous RNF138 function with a mutant (RNF138-H36E) or shRNA infection significantly upregulates the CaV2.1 protein level and enhances CaV2.1 protein stability. Disrupting endogenous RNF138 function also effectively rescues the defective protein expression of EA2 mutants, as well as fully reversing EA2 mutant-induced excessive proteasomal degradation of CaV2.1 WT subunits. RNF138-H36E coexpression only partially restores the dominant-negative effect of EA2 mutants on CaV2.1 WT functional expression, which can be attributed to defective membrane trafficking of CaV2.1 WT in the presence of EA2 mutants. We propose that RNF138 plays a critical role in the homeostatic regulation of CaV2.1 protein level and functional expression and that RNF138 serves as the primary E3 ubiquitin ligase promoting EA2-associated aberrant degradation of human CaV2.1 subunits.SIGNIFICANCE STATEMENT Loss-of-function mutations in the human CaV2.1 subunit are linked to episodic ataxia type 2 (EA2), a dominantly inherited disease characterized by paroxysmal attacks of ataxia and nystagmus. EA2-causing mutants may exert dominant-negative effects on the CaV2.1 wild-type subunit via aberrant proteasomal degradation. The molecular nature of the CaV2.1 ubiquitin-proteasome degradation pathway is currently unknown. The present study reports the first identification of an E3 ubiquitin ligase for CaV2.1, RNF138. CaV2.1 protein stability is dynamically regulated by RNF138 and auxiliary α2δ and β subunits. We provide a proof of concept that protecting the human CaV2.1 subunit from excessive proteasomal degradation with specific interruption of endogenous RNF138 function may partially contribute to the future development of a novel therapeutic strategy for EA2 patients.

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KCa channels as therapeutic targets in episodic ataxia type-2.

Publications

KCa channels as therapeutic targets in episodic ataxia type-2.

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