The expression of the rare caveolin-3 variant T78M alters cardiac ion channels function and membrane excitability.
The expression of the rare caveolin-3 variant T78M alters cardiac ion channels function and membrane excitability.
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DOI：
10.1093/cvr/cvx122
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发表时间：
2017-08-01
影响因子：
10.8
通讯作者：
Barbuti A
中科院分区：
文献类型：
--
作者：
Campostrini G;Bonzanni M;Lissoni A;Bazzini C;Milanesi R;Vezzoli E;Francolini M;Baruscotti M;Bucchi A;Rivolta I;Fantini M;Severi S;Cappato R;Crotti L;J Schwartz P;DiFrancesco D;Barbuti A
小窝蛋白病是由小窝蛋白-3 （cav-3）基因改变引起的遗传疾病家族。T78M cav-3变异与骨骼肌和心肌病变有关，但其功能贡献，特别是对心脏疾病的贡献，仍然存在争议。在这里，我们评估了T78M cav-3变异对心脏离子通道功能和膜兴奋性的影响。我们将野生型（WT）或T78M型cav-3转染到小窝蛋白-1敲除的小鼠胚胎成纤维细胞中，通过免疫荧光和电镜观察发现，两者都在质膜上表达并形成小窝。已知与cav-3相互作用和共免疫沉淀的两个离子通道hKv1.5和hHCN4也与T78M cav-3相互作用并驻留在脂筏中。电生理分析表明，T78M cav-3使hKv1.5通道在更多的超极化电位下激活和失活，hHCN4通道在更多的去极化电位下激活，且以显性方式发生。在自发跳动的新生儿心肌细胞中，T78M cav-3的表达显著增加了动作电位峰间变异性，但既没有改变平均速率，也没有改变最大舒张电位。我们还发现，在一小部分室上性心律失常患者中，T78M cav-3变异比一般人群更常见。最后，对窦房细胞和心房细胞模型的计算机分析证实，t78m依赖性的变化与促心律失常的作用是一致的。该研究表明，T78M cav-3诱导离子通道功能的复杂修饰，最终改变膜的兴奋性。因此，T78M cav-3的存在可以产生一种易感底物，与其他结构改变和/或基因突变一起，可能会导致心律失常。
Caveolinopathies are a family of genetic disorders arising from alterations of the caveolin-3 (cav-3) gene. The T78M cav-3 variant has been associated with both skeletal and cardiac muscle pathologies but its functional contribution, especially to cardiac diseases, is still controversial. Here, we evaluated the effect of the T78M cav-3 variant on cardiac ion channel function and membrane excitability. We transfected either the wild type (WT) or T78M cav-3 in caveolin-1 knock-out mouse embryonic fibroblasts and found by immunofluorescence and electron microscopy that both are expressed at the plasma membrane and form caveolae. Two ion channels known to interact and co-immunoprecipitate with the cav-3, hKv1.5 and hHCN4, interact also with T78M cav-3 and reside in lipid rafts. Electrophysiological analysis showed that the T78M cav-3 causes hKv1.5 channels to activate and inactivate at more hyperpolarized potentials and the hHCN4 channels to activate at more depolarized potentials, in a dominant way. In spontaneously beating neonatal cardiomyocytes, the expression of the T78M cav-3 significantly increased action potential peak-to-peak variability without altering neither the mean rate nor the maximum diastolic potential. We also found that in a small cohort of patients with supraventricular arrhythmias, the T78M cav-3 variant is more frequent than in the general population. Finally, in silico analysis of both sinoatrial and atrial cell models confirmed that the T78M-dependent changes are compatible with a pro-arrhythmic effect. This study demonstrates that the T78M cav-3 induces complex modifications in ion channel function that ultimately alter membrane excitability. The presence of the T78M cav-3 can thus generate a susceptible substrate that, in concert with other structural alterations and/or genetic mutations, may become arrhythmogenic.
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影响因子：
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作者：
Hedley, Paula L.;Kanters, Jorgen K.;Christiansen, Michael
通讯作者：
Christiansen, Michael
影响因子：
5
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影响因子：
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Dostal, David E.
影响因子：
158.5
作者：
Milanesi, R;Baruscotti, M;DiFrancesco, D
通讯作者：
DiFrancesco, D
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5.5
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Macri, Vincenzo;Mahida, Saagar N.;Zhang, Michael L.;Sinner, Moritz F.;Dolmatova, Elena V.;Tucker, Nathan R.;McLellan, Micheal;Shea, Marisa A.;Milan, David J.;Lunetta, Kathryn L.;Benjamin, Emelia J.;Ellinor, Patrick T.
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Ellinor, Patrick T.