Spinocerebellar ataxia-13 Kv3.3 potassium channels: arginine-to-histidine mutations affect both functional and protein expression on the cell surface
Spinocerebellar ataxia-13 Kv3.3 potassium channels: arginine-to-histidine mutations affect both functional and protein expression on the cell surface
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DOI：
10.1042/bj20130034
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发表时间：
2013-09-01
影响因子：
4.1
通讯作者：
Thornhill, William B.
中科院分区：
文献类型：
--
作者：
Zhao, Jian;Zhu, Jing;Thornhill, William B.
The voltage-gated potassium channel K(v)3.3 is the causative gene of SCA13 (spinocerebellar ataxia type 13), an autosomal dominant neurological disorder. The four dominant mutations identified to date cause K(v)3.3 channels to be non-functional or have altered gating properties in Xenopus oocytes. In the present paper, we report that SCA13 mutations affect functional as well as protein expression of K(v)3.3 channels in a mammalian cell line. The reduced protein level of SCA13 mutants is caused by a shorter protein half-life, and blocking the ubiquitin proteasome pathway increases the total protein of SCA13 mutants more than wild-type. SCA13 mutated amino acids are highly conserved, and the side chains of these residues play a critical role in the stable expression of K(v)3.3 proteins. In addition, we show that mutant K(v)3.3 protein levels could be partially rescued by treatment with the chemical chaperone TMAO (trimethylamine N-oxide) and to a lesser extent with co-expression of K(v)3.1b. Thus our results suggest that amino acid side chains of SCA13 positions affect the protein half-life and/or function of K(v)3.3, and the adverse effect on protein expression cannot be fully rescued.
