Piezo channels and GsMTx4: Two milestones in our understanding of excitatory mechanosensitive channels and their role in pathology.
Piezo channels and GsMTx4: Two milestones in our understanding of excitatory mechanosensitive channels and their role in pathology.
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DOI：
10.1016/j.pbiomolbio.2017.07.011
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发表时间：
2017-11
影响因子：
3.8
通讯作者：
Suchyna TM
中科院分区：
文献类型：
--
作者：
Suchyna TM
压电通道的发现及其对抑制剂GsMTx 4的敏感性的报道是研究非选择性阳离子机械敏感通道（MSC）在正常生理和发病机制中的重要里程碑。多年来，GsMTx 4一直被用于研究阳离子MSC的功能作用，特别是在肌肉组织中，但对其靶点或抑制机制知之甚少。当在异源系统中表达时，压电通道对双层应力的敏感性及其强大的机械敏感性是确定GsMTx 4作用机制的关键。然而，关于Piezo在肌肉功能中的作用仍然存在问题，这是由于GsMTx 4对膜机械酶的非选择性抑制以及遗传敲低对MCS通道类型的影响。证据支持压电样活动，至少在肌肉的发育阶段，提出。虽然GsMTx 4在肌肉病理学中的MSC靶点尚不清楚，但其肌肉保护作用在最近对正常心肌细胞和营养不良骨骼肌的两项原位研究中得到了明确证明。GsMTx 4对肌细胞的保护作用可能是由于其对阳离子MSC如Piezo和TRP的抑制作用以及其对K+选择性MSC如K2 P和SAKCa的复极化的增强作用的综合作用。奇怪的是，GsMTx 4对许多生理功能的有效体外作用似乎与其对正常动物生理学缺乏原位副作用相冲突。未来的调查肌膜力学的细胞骨架控制和怀疑包括MSC在膜微/纳米尺寸的域具有不同的机械性能将有助于我们理解这种二分法。
Discovery of Piezo channels and the reporting of their sensitivity to the inhibitor GsMTx4 were important milestones in the study of non-selective cationic mechanosensitive channels (MSCs) in normal physiology and pathogenesis. GsMTx4 had been used for years to investigate the functional role of cationic MSCs, especially in muscle tissue, but with little understanding of its target or inhibitory mechanism. The sensitivity of Piezo channels to bilayer stress and its robust mechanosensitivity when expressed in heterologous systems were keys to determining GsMTx4’s mechanism of action. However, questions remain regarding Piezo’s role in muscle function due to the non-selective nature of GsMTx4 inhibition toward membrane mechanoenzymes and the implication of MCS channel types by genetic knockdown. Evidence supporting Piezo like activity, at least in the developmental stages of muscle, is presented. While the MSC targets of GsMTx4 in muscle pathology are unclear, its muscle protective effects are clearly demonstrated in two recent in situ studies on normal cardiomyocytes and dystrophic skeletal muscle. The muscle protective function may be due to the combined effect of GsMTx4’s inhibitory action on cationic MSCs like Piezo and TRP, and its potentiation of repolarizing K+ selective MSCs like K2P and SAKCa. Paradoxically, the potent in vitro action of GsMTx4 on many physiological functions seems to conflict with its lack of in situ side-effects on normal animal physiology. Future investigations into cytoskeletal control of sarcolemma mechanics and the suspected inclusion of MSCs in membrane micro/nano sized domains with distinct mechanical properties will aide our understanding of this dichotomy.
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DOI：
10.1152/physiol.00006.2012
发表时间：
2012-10
期刊：
Physiology (Bethesda, Md.)
影响因子：
--
作者：
Eastwood AL;Goodman MB
通讯作者：
Goodman MB
影响因子：
3.4
作者：
Charras, Guillaume T.;Coughlin, Margaret;Mahadevan, L.
通讯作者：
Mahadevan, L.
影响因子：
11.4
作者：
Chemin, J;Girard, C;Lazdunski, M
通讯作者：
Lazdunski, M
影响因子：
11.4
作者：
Fink, M;Duprat, F;Lazdunski, M
通讯作者：
Lazdunski, M
影响因子：
2.9
作者：
Biro，Mate;Romeo，Yves;Paluch，Ewa K.
通讯作者：
Paluch，Ewa K.