Homer proteins mediate the interaction between STIM1 and Cav1.2 channels
Homer proteins mediate the interaction between STIM1 and Cav1.2 channels
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DOI：
10.1016/j.bbamcr.2015.02.014
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发表时间：
2015-05-01
影响因子：
5.1
通讯作者：
Rosado, Juan A.
中科院分区：
文献类型：
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作者：
Dionisio, Natalia;Smani, Tarik;Rosado, Juan A.
STIM1是细胞内普遍存在的Ca2+传感器，对激动剂敏感，Ca2+储存，将Ca2+室的填充状态传递给质膜储存操作的Ca2+ (SOC)通道。STIM1被认为是存储操作和电压操作的Ca2+内流之间的交汇点，两者都诱导SOC通道的激活，同时抑制Ca(v)1.2通道。在这里，我们报道了Homer蛋白在STIM1和Ca(v)1.2通道之间的通信中发挥相关作用。瞬时表达Ca(v)1.2通道亚单位α(1)、β(2)和α (2) δ -1的HEK-293细胞在高浓度KCl处理下表现出显著的Ca2+进入。在表达Ca(v)1.2的细胞中，用thapsigargin （TG）处理，诱导细胞内Ca2+储存的被动放电，导致Ca2+内流显著大于不表达Ca(v)1.2通道的细胞，硝苯地平和地尔硫卓消除了这种差异。TG处理诱导Homer1与STIM1和Ca(v)1.2 α(1)亚基共免疫沉淀。通过将模拟PPXXF基序脯氨酸丰富序列的合成PPKKFR肽引入细胞或使用siRNA Homer1来损伤Homer功能，可以减少STIM1与Ca(v)1.2 α(1)亚基的关联。这些发现表明，Homer对于两种蛋白质之间的联系很重要。最后，siRNA Homer1或PPKKFR肽处理增强了Ca(v)1.2表达细胞中硝苯地平敏感成分的TG反应。总之，这些发现为Homer1支持STIM1调控Ca(v)1.2通道的新作用提供了证据。(C) 2015 Elsevier B.V.版权所有
STIM1 is a ubiquitous Ca2+ sensor of the intracellular, agonist-sensitive, Ca2+ stores that communicates the filling state of the Ca2+ compartments to plasma membrane store-operated Ca2+ (SOC) channels. STIM1 has been presented as a point of convergence between store-operated and voltage-operated Ca2+ influx, both inducing activation of SOC channels while suppressing Ca(v)1.2 channels. Here we report that Homer proteins play a relevant role in the communication between STIM1 and Ca(v)1.2 channels. HEK-293 cells transiently expressing Ca(v)1.2 channel subunits alpha(1), beta(2) and alpha(2)delta-1 exhibited a significant Ca2+ entry upon treatment with a high concentration of KCl. In Ca(v)1.2-expressing cells, treatment with thapsigargin (TG), to induce passive discharge of the intracellular Ca2+ stores, resulted in Ca2+ influx that was significantly greater than in cells not expressing Ca(v)1.2 channels, a difference that was abolished by nifedipine and diltiazem. Treatment with TG induces co-immunoprecipitation of Homer1 with STIM1 and the Ca(v)1.2 alpha(1) subunit. Impairment of Homer function by introduction of the synthetic PPKKFR peptide into cells, which emulates the praline-rich sequences of the PPXXF motif, or using siRNA Homer1, reduced the association of STIM1 and the Ca(v)1.2 alpha(1) subunit. These findings indicate that Homer is important for the association between both proteins. Finally, treatment with siRNA Homer1 or the PPKKFR peptide enhanced the nifedipine-sensitive component of TG response in Ca(v)1.2-expressing cells. Altogether, these findings provide evidence for a new role of Homer1 supporting the regulation of Ca(v)1.2 channels by STIM1. (C) 2015 Elsevier B.V. All rights reserved.