Dysfunction of store-operated calcium channel in muscle cells lacking mg29
Dysfunction of store-operated calcium channel in muscle cells lacking mg29
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DOI：
10.1038/ncb788
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发表时间：
2002-05-01
影响因子：
21.3
通讯作者：
Ma, JJ
中科院分区：
文献类型：
--
作者：
Pan, Z;Yang, DM;Ma, JJ
位于质膜（PM）的储存操作钙通道（SOC）在内质网或肌浆网（ER/SR）的细胞内钙储存耗尽后介导细胞外钙的容性进入（1,2）。PM和ER/SR之间的密切相互作用对于钙信号通路的运作至关重要（3-5）。Mitsugumin 29 （MG29）是一种突触素家族相关蛋白，位于骨骼肌PM和SR之间的连接处（6,7）。在这里，我们确定了骨骼肌中的SOC，并表征了MG29和位于SR中的ryanodine受体（RyR）对其的调节。MG29的靶向缺失改变了连接膜结构，导致SOC和SR钙稳态严重失调，并增加了肌肉对疲劳刺激的易感性(8)。在缺乏1型和3型RyRs的肌肉细胞中也发现了严重的SOC功能障碍，这表明SOC激活需要PM和SR之间完整的相互作用，并且与RyRs的构象改变有关。虽然SOC缺陷似乎与短期兴奋收缩耦合无关，但通过SOC缓慢累积的钙进入对长期钙稳态至关重要，因此SOC活动的减少会加剧高强度运动条件下的肌肉疲劳。
The store-operated calcium channel (SOC) located in the plasma membrane (PM) mediates capacitative entry of extracellular calcium after depletion of intracellular calcium stores in the endoplasmic or sarcoplasmic reticulum (ER/SR)(1,2). An intimate interaction between the PM and the ER/SR is essential for the operation of this calcium signalling pathway(3-5). Mitsugumin 29 (MG29) is a synaptophysin-family-related protein located in the junction between the PM and SR of skeletal muscle(6,7). Here, we identify SOC in skeletal muscle and characterise its regulation by MG29 and the ryanodine receptor (RyR) located in the SR. Targeted deletion of mg29 alters the junctional membrane structure, causes severe dysfunction of SOC and SR calcium homeostasis and increases the susceptibility of muscle to fatigue stimulation(8). Severe dysfunction of SOC is also identified in muscle cells lacking both type 1 and type 3 RyRs, indicating that SOC activation requires an intact interaction between the PM and the SR, and is linked to conformational changes of RyRs. Whereas defective SOC seems to be inconsequential to short-term excitation contraction coupling, the slow cumulative calcium entry through SOC is crucial for long-term calcium homeostasis, such that reduced SOC activity exaggerates muscle fatigue under conditions of intensive exercise.