Initiation of human myoblast differentiation via dephosphorylation of Kir2.1 K+ channels at tyrosine 242
Initiation of human myoblast differentiation via dephosphorylation of Kir2.1 K+ channels at tyrosine 242
复制标题
DOI：
10.1242/dev.011387
复制
发表时间：
2008-03-01
期刊：
影响因子：
4.6
通讯作者：
Bernheim, Laurent
中科院分区：
文献类型：
--
作者：
Hinard, Valerie;Belin, Dominique;Bernheim, Laurent
成肌细胞的分化对骨骼肌的形成和修复至关重要。导致人成肌细胞分化的最早可检测事件是Kir2.1通道活性的上调，其导致成肌细胞静息电位的负向偏移（超极化）。在探索了各种机制后，我们发现Kir2.1的这种上调是由于通道本身的去磷酸化。应用染料木素，酪氨酸激酶抑制剂，增加Kir2.1的活性，并触发分化过程，而应用bpV（Phen），酪氨酸磷酸酶抑制剂，有相反的效果。我们可以表明，Kir2.1活性的增加需要酪氨酸242的去磷酸化，取代此酪氨酸在Kir2.1的苯丙氨酸废除抑制bpV（Phen）。最后，我们发现，在内源性Kir2.1通道的酪氨酸磷酸化水平显着降低分化过程中相比，增殖。我们提出Kir2.1通道已经存在于增殖的未分化的人成肌细胞的膜上，但处于沉默状态，Kir2.1酪氨酸242去磷酸化触发分化。
Myoblast differentiation is essential to skeletal muscle formation and repair. The earliest detectable event leading to human myoblast differentiation is an upregulation of Kir2.1 channel activity, which causes a negative shift ( hyperpolarization) of the resting potential of myoblasts. After exploring various mechanisms, we found that this upregulation of Kir2.1 was due to dephosphorylation of the channel itself. Application of genistein, a tyrosine kinase inhibitor, increased Kir2.1 activity and triggered the differentiation process, whereas application of bpV(Phen), a tyrosine phosphatase inhibitor, had the opposite effects. We could show that increased Kir2.1 activity requires dephosphorylation of tyrosine 242; replacing this tyrosine in Kir2.1 by a phenylalanine abolished inhibition by bpV(Phen). Finally, we found that the level of tyrosine phosphorylation in endogenous Kir2.1 channels is considerably reduced during differentiation when compared with proliferation. We propose that Kir2.1 channels are already present at the membrane of proliferating, undifferentiated human myoblasts but in a silent state, and that Kir2.1 tyrosine 242 dephosphorylation triggers differentiation.