7DHC-induced changes of Kv1.3 operation contributes to modified T cell function in Smith-Lemli-Opitz syndrome
7DHC-induced changes of Kv1.3 operation contributes to modified T cell function in Smith-Lemli-Opitz syndrome
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DOI：
10.1007/s00424-016-1851-4
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发表时间：
2016-08-01
影响因子：
4.5
通讯作者：
Hajdu, Peter
中科院分区：
文献类型：
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作者：
Balajthy, Andras;Somodi, Sandor;Hajdu, Peter
在体外操纵膜固醇水平影响离子通道的调节，从而某些细胞功能，然而，一个全面的研究，证实这些结果的病理生理意义是失踪。Smith-Lemli-Opitz综合征（SLOS）中7-脱氢胆固醇（7 DHC）还原酶的功能障碍导致质膜中7-脱氢胆固醇水平升高。从SLOS患者中分离T淋巴细胞，以评估体内改变的膜固醇组合物对电压门控Kv1.3通道和离子通道依赖性促有丝分裂反应的作用。我们发现Kv1.3激活的动力学和平衡参数在SLOS细胞中发生了变化。当对照/健康T细胞负载有7 DHC时，观察到Kv1.3操作中的相同变化。去除Kv1.3上假定的甾醇结合位点导致不受膜甾醇水平升高影响的表型。功能测定显示T细胞的活化和增殖率受损，可能部分是由于修改的Kv1.3操作。我们的结论是，改变膜固醇组成阻碍Kv1.3的操作以及离子通道控制的T细胞功能。
In vitro manipulation of membrane sterol level affects the regulation of ion channels and consequently certain cellular functions; however, a comprehensive study that confirms the pathophysiological significance of these results is missing. The malfunction of 7-dehydrocholesterol (7DHC) reductase in Smith-Lemli-Opitz syndrome (SLOS) leads to the elevation of the 7-dehydrocholesterol level in the plasma membrane. T lymphocytes were isolated from SLOS patients to assess the effect of the in vivo altered membrane sterol composition on the operation of the voltage-gated Kv1.3 channel and the ion channel-dependent mitogenic responses. We found that the kinetic and equilibrium parameters of Kv1.3 activation changed in SLOS cells. Identical changes in Kv1.3 operation were observed when control/healthy T cells were loaded with 7DHC. Removal of the putative sterol binding sites on Kv1.3 resulted in a phenotype that was not influenced by the elevation in membrane sterol level. Functional assays exhibited impaired activation and proliferation rate of T cells probably partially due to the modified Kv1.3 operation. We concluded that the altered membrane sterol composition hindered the operation of Kv1.3 as well as the ion channel-controlled T cell functions.