Nuclear sequestration of β-subunits by Rad and Rem is controlled by 14-3-3 and calmodulin and reveals a novel mechanism for Ca2+ channel regulation

被引:81
作者
Béguin, P
Mahalakshmi, RN
Nagashima, K
Cher, DHK
Ikeda, H
Yamada, Y
Seino, Y
Hunziker, W
机构
[1] Inst Mol & Cell Biol, Epithelial Cell Biol Lab, Singapore 138673, Singapore
[2] Kyoto Univ, Grad Sch Med, Dept Diabet & Clin Nutr, Sakyo Ku, Kyoto 6068507, Japan
关键词
14-3-3; calcium channel; calmodulin; Rad; Rem;
D O I
10.1016/j.jmb.2005.10.013
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Voltage-gated Ca2+ channels (VDCCs) are heteromultimeric proteins that mediate Ca2+ influx into cells upon membrane depolarization. These channels are involved in various cellular events, including gene expression, regulation of hormone secretion and synaptic transmission. Kir/Gem, Rad, Rem, and Rem2 belong to the RGK family of Ras-related small G proteins. RGK proteins interact with the beta-subunits and downregulate VDCC activity. Kir/Gem was proposed to prevent surface expression of functional Ca2+ channels, while for Rem2 the mechanism remain controversial. Here, we have analyzed the mechanism by which Rad and Rem regulate VDCC activity. We show that, similar to Kir/Gem and Rem2, 14-3-3 and CaM binding regulate the subcellular distribution of Rad and Rem, which both inhibit Ca2+ channel activity by preventing its expression on the cell surface. This function is regulated by calmodulin and 14-3-3 binding only for Rad and not for Rem. Interestingly, nuclear targeting of Rad and Rem can relocalize and sequester the beta-subunit to the nucleus, thus providing a novel mechanism for Ca2+ channel downregulation. (c) 2005 Elsevier Ltd. All rights reserved.
引用
收藏
页码:34 / 46
页数:13
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