Laboratory for Developmental Neurobiology, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
Biochem Biophys Res Commun. 2011 Jul 15;410(4):754-8. doi: 10.1016/j.bbrc.2011.06.043. Epub 2011 Jun 13.
Spinocerebellar ataxia type 15 (SCA15) is a group of human neurodegenerative disorders characterized by a slowly progressing pure cerebellar ataxia. The inositol 1,4,5-trisphosphate (IP(3)) receptor type 1 (IP(3)R1) is an intracellular IP(3)-induced Ca(2+) release channel that was recently identified as a causative gene for SCA15. In most case studies, a heterozygous deletion of the IP(3)R1 gene was identified. However, one Japanese SCA15 family was found to have a Pro to Leu (P1059L) substitution in IP(3)R1. To investigate the effect of the P1059L mutation, we analyzed the channel properties of the mutant human IP(3)R1 by expressing it in an IP(3)R-deficient B lymphocyte cell line. The P1059L mutant was a functional Ca(2+) release channel with a twofold higher IP(3) binding affinity compared to wild-type IP(3)R1. The cooperative dependence of the Ca(2+) release activity of the mutant on IP(3) concentration was reduced, but both wild-type and mutant receptors produced similar B cell receptor-induced Ca(2+) signals. These results demonstrate that the Ca(2+) release properties of IP(3)R1 are largely unaffected by the P1059L mutation.
脊髓小脑性共济失调 15 型（SCA15）是一组人类神经退行性疾病，其特征为进行性缓慢的纯小脑共济失调。三磷酸肌醇（IP（3））受体 1 型（IP（3）R1）是一种细胞内 IP（3）诱导的 Ca（2+）释放通道，最近被确定为 SCA15 的致病基因。在大多数病例研究中，发现 IP（3）R1 基因的杂合缺失。然而，一个日本的 SCA15 家族被发现存在 IP（3）R1 中的脯氨酸到亮氨酸（P1059L）取代。为了研究 P1059L 突变的影响，我们通过在缺乏 IP（3）R 的 B 淋巴细胞系中表达该突变体，分析了突变型人 IP（3）R1 的通道特性。与野生型 IP（3）R1 相比，P1059L 突变体是一种功能性 Ca（2+）释放通道，对 IP（3）的结合亲和力高两倍。突变体的 Ca（2+）释放活性对 IP（3）浓度的协同依赖性降低，但野生型和突变型受体均产生相似的 B 细胞受体诱导的 Ca（2+）信号。这些结果表明，IP（3）R1 的 Ca（2+）释放特性受 P1059L 突变的影响不大。
