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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Bidirectional signaling between calcium channels of skeletal muscle requires multiple direct and indirect interactions
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Bidirectional signaling between calcium channels of skeletal muscle requires multiple direct and indirect interactions

机译：骨骼肌钙通道之间的双向信号传导需要多个直接和间接相互作用

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摘要

We have defined regions of the skeletal muscle ryanodine receptor (RyR1) essential for bidirectional signaling with dihydropyridine receptors (DHPRs) and for the organization of DHPR into tetrad arrays by expressing RyR1-RyR3 chimerae in dyspedic myotubes. RyR1-RyR3 constructs bearing RyR1 residues 1-1681 restored wild-type DHPR tetrad arrays and, in part, skeletal-type excitation-contraction (EC) coupling (orthograde signaling) but failed to enhance DHPR Ca~(2+) currents (retrograde signaling) to WT RyR1 levels. Within this region, the D2 domain (amino acids 1272-1455), although ineffective on its own, dramatically enhanced the formation of tetrads and EC coupling rescue by constructs that otherwise are only partially effective. These findings suggest that the orthograde signal and DHPR tetrad formation require the contributions of numerous RyR regions. Surprisingly, we found that RyR3, although incapable of supporting EC coupling or tetrad formation, restored a significant level of Ca~(2+) current, revealing a functional interaction with the skeletal muscle DHPR. Thus, our data support the hypotheses that (ⅰ) the structural/functional link between RyR1 and the skeletal muscle DHPR requires multiple interacting regions, (ⅱ) the D2 domain of RyR1 plays a key role in stabilizing this interaction, and (ⅲ) a form of retrograde signaling from RyR3 to the DHPR occurs in the absence of direct protein-protein interactions.
机译：我们已经定义了骨骼肌ryanodine受体（RyR1）的区域，该区域对于通过二氢吡啶受体（DHPRs）进行双向信号传递以及通过在非典型的肌管中表达RyR1-RyR3嵌合体将DHPR组织成四联体阵列至关重要。携带RyR1残基1-1681的RyR1-RyR3构建体恢复了野生型DHPR四元阵列，部分恢复了骨骼型激发-收缩（EC）耦合（正向信号转导），但未能增强DHPR Ca〜（2+）电流（逆行）信令）到WT RyR1级别。在该区域内，D2结构域（氨基酸1272-1455）虽然本身无效，但可通过其他方式仅部分有效的构建体显着增强四链体的形成和EC偶联拯救。这些发现表明正统信号和DHPR四联体的形成需要许多RyR区的贡献。出人意料的是，我们发现RyR3尽管不能支持EC偶联或四联体形成，却恢复了显着水平的Ca〜（2+）电流，揭示了与骨骼肌DHPR的功能相互作用。因此，我们的数据支持以下假设：（ⅰ）RyR1和骨骼肌DHPR之间的结构/功能联系需要多个相互作用区域，（ⅱ）RyR1的D2结构域在稳定这种相互作用中起关键作用，并且（ⅲ）从RyR3到DHPR的逆行信号传导形式在没有直接的蛋白质-蛋白质相互作用的情况下发生。

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