Covalent cross-bridge regulation in smooth muscle.
Covalent cross-bridge regulation in smooth muscle.
复制标题
平滑肌中的共价跨桥调节。
DOI：
10.1111/j.1749-6632.1990.tb42365.x
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发表时间：
1990
影响因子：
5.2
通讯作者：
Murphy,RA
中科院分区：
文献类型：
--
作者：
McDaniel,NL;Rembold,CM;Murphy,RA
平滑肌缺乏肌钙蛋白，这是一种钙离子结合细丝成分，可调节脊椎动物横纹肌的跨桥循环。l现在有非常强有力的证据表明Ca？+通过共价跨桥修饰调节平滑肌跨桥循环。肌球蛋白轻链激酶（MLCK）对20 kDa肌球蛋白调节轻链的Ca 2 +-钙调蛋白依赖性磷酸化触发平滑肌收缩。最初发现磷酸化在体外增加肌球蛋白ATP酶速率。这一结果表明，磷酸化作为一个简单的开关，通过构象变化打开了一个跨桥。磷酸化开关假说的预测是只有磷酸化的交叉桥与细丝相互作用，使得力与磷酸化成正比（如图1A所示）。然而，完整平滑肌对激动剂刺激的通常反应是与肌浆钙浓度（[Ca？+]）瞬时升高相关的快速收缩。和磷酸化。尽管[CaZ+]、磷酸化、跨桥循环速率或缩短速度2.6和ATP消耗降低至低稳态值，但力在持续刺激下保持高。这被称为锁存状态（图1B）。6闩锁最初被定义为没有升高的磷酸化水平的Ca 2+依赖性力维持;一种未鉴定的Ca 2+依赖性调节机制被假定来解释闩锁状态。6随后的研究表明，这是误导。初始Ca 2+和磷酸化瞬变对于高水平力的发展不是必需的（图1C）。8，9因此，闩锁不是简单地通过横桥阻滞或其他一些连接来维持先前发展的力，而是依赖于Ca？+-依赖性磷酸化早期研究中人为的高静息磷酸化水平掩盖了闩锁状态下的微小增加。稳定状态力对磷酸化有陡峭的依赖性，并且仅在30%磷酸化时产生接近最大的力。
Smooth muscle lacks troponin, the Ca2+-binding thin filament constituent that regulates cross-bridge cycling in vertebrate striated musc1e. l There is now very strong evidence that Ca?+ regulates smooth muscle cross-bridge cycling by covalent cross-bridge modification. Ca2+-calmodulin-dependent phosphorylation of the 20 kDa myosin regulatory light chain by myosin light chain kinase (MLCK) triggers contraction in smooth muscle. Phosphorylation was initially found to increase the myosin ATPase rate in uitro. This result suggested that phosphorylation acted as a simple switch to turn a cross-bridge “on” through a conformational~ hange.~-~ A prediction of the phosphorylation switch hypothesis is that only phosphorylated cross-bridges interact with the thin filaments so that force would be directly proportional to phosphorylation (as in FIG. 1A). The usual response of intact smooth muscle to agonist stimulation, however, is rapid contraction associated with transient elevations in myoplasmic calcium concentration ([Ca?+]) and phosphorylation. Force remains high with sustained stimulation despite decreases in [CaZ+], phosphorylation, cross-bridge cycling rates or shortening velocity, 2.6 and ATP consumption’to low steady state values. This was termed the latch state (FIG. 1B). 6Latch was initially defined as Ca2+-dependent force maintenance without elevated phosphorylation levels; an unidentified Ca2+-dependent regulatory mechanism was postulated to explain the latch state. 6 Subsequent studies showed that this was misleading. The initial Ca2+ and phosphorylation transients were not necessary for the development of high levels of force (FIG. lC). 8, 9 Thus, latch was not simply the maintenance of previously developed force by cross-bridge arrest or some other linkage, but rather a state of slowed cross-bridge turnover dependent on small increases in Ca?+-dependent phosphorylation. Artifactual highresting phosphorylation levels in early studies masked the small increases that underlie the latch state. lO% ll There is a steep dependence of steady state force on phosphorylation, and near maximal force is generated with only 30% phosphorylation.