Rem uncouples excitation-contraction coupling in adult skeletal muscle fibers.
Rem uncouples excitation-contraction coupling in adult skeletal muscle fibers.
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DOI：
10.1085/jgp.201411314
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发表时间：
2015-07
期刊：
影响因子：
--
通讯作者：
Bannister RA
中科院分区：
文献类型：
--
作者：
Beqollari D;Romberg CF;Filipova D;Meza U;Papadopoulos S;Bannister RA
RGK蛋白Rem通过与辅助的β1a亚基相互作用，使CaV1.1的电压感受器与RYR1介导的肌浆网钙释放解偶联。在骨骼肌中，兴奋-收缩(EC)偶联需要去极化诱导的L钙通道(CaV1.1)的构象重排通过瞬时的蛋白质-蛋白质相互作用传递到肌浆网(SR)的1型兰诺定敏感的钙释放通道(RYR1R)。尽管CaV1.1和RYR1之间构象偶联的分子机制已经被深入研究了25年，但这种信号转导是通过CaV1.1和RYR1中主要的电压敏感的α1S亚基之间的直接相互作用还是通过中间蛋白发生的问题仍然存在。大量证据支持这样的观点，即CaV1.1的辅助β1a亚单位是这种分子间沟通的管道。然而，β1a的直接作用很难测试，因为β1a还有另外两个功能，这两个功能是CaV1.1和RYR1间构象偶联的先决条件。具体地说，β1a促进了CaV1.1的有效膜表达，并促进了质膜-SR连接内CaV1.1通道的四射超微结构排列。在这篇文章中，我们证明了在成年小鼠趾短屈肌纤维中过表达RGK蛋白Rem，一种已建立的β亚单位相互作用的蛋白，显著减少了电压诱导的肌浆钙瞬变，而不显著影响CaV1.1靶向，膜内门控电荷移动，或可释放的SR钙存储含量。相反，β1a结合缺陷的Rem三重突变体(R200A/L227A/H229A)对膜去极化反应中的肌浆钙释放几乎没有影响。因此，Rem通过与β1a的相互作用，有效地将CaV1.1的电压传感器从RYR1介导的SR钙释放中分离出来。我们的发现揭示了表达Rem的成人肌肉作为一个实验系统，可能被证明在定义β1a亚单位在骨架型EC偶联中的确切作用方面有用。
The RGK protein Rem uncouples the voltage sensors of CaV1.1 from RYR1-mediated sarcoplasmic reticulum Ca2+ release via its ability to interact with the auxiliary β1a subunit. In skeletal muscle, excitation–contraction (EC) coupling requires depolarization-induced conformational rearrangements in L-type Ca2+ channel (CaV1.1) to be communicated to the type 1 ryanodine-sensitive Ca2+ release channel (RYR1) of the sarcoplasmic reticulum (SR) via transient protein–protein interactions. Although the molecular mechanism that underlies conformational coupling between CaV1.1 and RYR1 has been investigated intensely for more than 25 years, the question of whether such signaling occurs via a direct interaction between the principal, voltage-sensing α1S subunit of CaV1.1 and RYR1 or through an intermediary protein persists. A substantial body of evidence supports the idea that the auxiliary β1a subunit of CaV1.1 is a conduit for this intermolecular communication. However, a direct role for β1a has been difficult to test because β1a serves two other functions that are prerequisite for conformational coupling between CaV1.1 and RYR1. Specifically, β1a promotes efficient membrane expression of CaV1.1 and facilitates the tetradic ultrastructural arrangement of CaV1.1 channels within plasma membrane–SR junctions. In this paper, we demonstrate that overexpression of the RGK protein Rem, an established β subunit–interacting protein, in adult mouse flexor digitorum brevis fibers markedly reduces voltage-induced myoplasmic Ca2+ transients without greatly affecting CaV1.1 targeting, intramembrane gating charge movement, or releasable SR Ca2+ store content. In contrast, a β1a-binding–deficient Rem triple mutant (R200A/L227A/H229A) has little effect on myoplasmic Ca2+ release in response to membrane depolarization. Thus, Rem effectively uncouples the voltage sensors of CaV1.1 from RYR1-mediated SR Ca2+ release via its ability to interact with β1a. Our findings reveal Rem-expressing adult muscle as an experimental system that may prove useful in the definition of the precise role of the β1a subunit in skeletal-type EC coupling.
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DOI：
10.1073/pnas.0504334102
发表时间：
2005-12-27
影响因子：
11.1
作者：
Cheng, WJ;Altafaj, X;Coronado, R
通讯作者：
Coronado, R
影响因子：
64.8
作者：
Béguin, P;Nagashima, K;Seino, S
通讯作者：
Seino, S
影响因子：
4.8
作者：
Chen, L;Estève, E;Pessah, IN
通讯作者：
Pessah, IN
DOI：
10.1085/jgp.103.1.125
发表时间：
1994-01
期刊：
The Journal of general physiology
影响因子：
--
作者：
García J;Tanabe T;Beam KG
通讯作者：
Beam KG
DOI：
10.1073/pnas.0403485101
发表时间：
2004-11-02
影响因子：
11.1
作者：
Cherednichenko, G;Hurne, AM;Pessah, IN
通讯作者：
Pessah, IN