Zhang Zhen-Ning, Li Qian, Liu Chao, Wang Hai-Bo, Wang Qiong, Bao Lan
Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai, People's Republic of China.
J Cell Sci. 2008 Oct 1;121(Pt 19):3243-52. doi: 10.1242/jcs.026856. Epub 2008 Sep 9.
Voltage-gated Na(+) channel (Na(v)) 1.8 contributes to the majority of the Na(+) current that underlies the depolarizing phase of action potentials. Na(v)1.8 is mainly distributed intracellularly and its current amplitude can be enhanced by the beta3 subunit. However, little is known about the mechanisms underlying its intracellular retention and the effects mediated by the beta3 subunit. Here, we show that the beta3 subunit promotes surface expression of Na(v)1.8 by masking its endoplasmic reticulum (ER)-retention/retrieval signal. The RRR motif in the first intracellular loop of Na(v)1.8 is responsible for retaining Na(v)1.8 in the ER and restricting its surface expression. The beta3 subunit facilitates surface expression of Na(v)1.8. The intracellular C-terminus of the beta3 subunit interacts with the first intracellular loop of Na(v)1.8 and masks the ER-retention/retrieval signal. Mutation of the RRR motif results in a significant increase in surface expression of Na(v)1.8 and abolishes the beta3-subunit-mediated effects. Thus, the beta3 subunit regulates surface expression of Na(v)1.8 by antagonizing its ER-retention/retrieval signal. These results reveal a novel mechanism for the effect of the Na(+) channel beta subunits on the alpha subunits.
电压门控性钠通道（Na(v)）1.8 对构成动作电位去极化相的大部分钠电流起作用。Na(v)1.8 主要分布于细胞内，其电流幅度可被β3 亚基增强。然而，关于其细胞内滞留的机制以及β3 亚基介导的效应知之甚少。在此，我们表明β3 亚基通过掩盖其内质网（ER）滞留/回收信号来促进 Na(v)1.8 的表面表达。Na(v)1.8 第一个细胞内环中的RRR 基序负责将 Na(v)1.8 滞留在内质网并限制其表面表达。β3 亚基促进 Na(v)1.8 的表面表达。β3 亚基的细胞内 C 末端与 Na(v)1.8 的第一个细胞内环相互作用并掩盖内质网滞留/回收信号。RRR 基序的突变导致 Na(v)1.8 的表面表达显著增加，并消除了β3 亚基介导的效应。因此，β3 亚基通过拮抗其内质网滞留/回收信号来调节 Na(v)1.8 的表面表达。这些结果揭示了钠通道β亚基对α亚基作用的一种新机制。
