Tang Wei, Sencer Serap, Hamilton Susan L
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas, USA.
Front Biosci. 2002 Jun 1;7:d1583-9. doi: 10.2741/tang.
Muscle excitation-contraction coupling is, in large part, regulated by the activity of two proteins. These are the ryanodine receptor (RyR), which is an intracellular Ca2+ release channel and the dihydropyridine receptor (DHPR), which is a voltage gated L-type calcium channel. In skeletal muscle, the physical association between RyR1 and L-type Ca2+ channels is required for muscle excitation-contraction coupling. RyRs also regulate intracellular Ca2+ homeostasis, thereby contributing to a variety of cellular functions in different tissues. A wide variety of modulators directly regulate RyR1 activity and, consequentially, alter both excitation-contraction coupling and calcium homeostasis. Calmodulin, one of these cellular modulators, is a ubiquitously expressed 17 kDa Ca2+ binding protein containing four E-F hands, which binds to RyR1 at both nanomolar and micromolar Ca2+ concentrations. Apocalmodulin (Ca2+ free calmodulin) is a partial agonist, while Ca2+calmodulin is an inhibitor of RyR1. This conversion of calmodulin from an activator to an inhibitor is due to Ca2+ binding to the two C-terminal sites on calmodulin. Calmodulin can also modulate the L-type Ca2+ channel in the transverse tubule membrane, producing either inactivation or facilitation of the channel upon elevation of the local Ca2+ concentrations. Calmodulin binds to a region on RyR1 corresponding to amino acids 3614-3643 and to a region in the carboxy-terminal tail of the L-type Ca2+ channel (1 subunit. However, these calmodulin binding motifs on both proteins bind to undetermined motifs on the other protein, suggesting that they represent more general protein-protein interaction motifs. These findings raise questions about the role of calmodulin in excitation-contraction coupling in skeletal muscle.
肌肉兴奋-收缩偶联在很大程度上受两种蛋白质活性的调节。这两种蛋白质分别是兰尼碱受体（RyR），它是一种细胞内钙离子释放通道；以及二氢吡啶受体（DHPR），它是一种电压门控L型钙通道。在骨骼肌中，RyR1与L型钙通道之间的物理关联是肌肉兴奋-收缩偶联所必需的。RyRs还调节细胞内钙离子稳态，从而在不同组织中参与多种细胞功能。多种调节剂直接调节RyR1的活性，进而改变兴奋-收缩偶联和钙稳态。钙调蛋白就是这些细胞调节剂之一，它是一种广泛表达的17 kDa钙离子结合蛋白，含有四个E-F手结构域，在纳摩尔和微摩尔钙离子浓度下均能与RyR1结合。脱钙钙调蛋白（无钙离子的钙调蛋白）是一种部分激动剂，而钙离子-钙调蛋白是RyR1的抑制剂。钙调蛋白从激活剂转变为抑制剂是由于钙离子与钙调蛋白的两个C末端位点结合。钙调蛋白还可以调节横管膜中的L型钙通道，在局部钙离子浓度升高时使该通道失活或促进其活性。钙调蛋白与RyR1上对应于氨基酸3614 - 3643的区域以及L型钙通道（α1亚基）羧基末端尾巴中的一个区域结合。然而，这两种蛋白质上的这些钙调蛋白结合基序与另一种蛋白质上未确定的基序结合，这表明它们代表更普遍的蛋白质-蛋白质相互作用基序。这些发现引发了关于钙调蛋白在骨骼肌兴奋-收缩偶联中作用的问题。
