Serum and glucocorticoid inducible kinases in the regulation of the cardiac sodium channel SCN5A
Serum and glucocorticoid inducible kinases in the regulation of the cardiac sodium channel SCN5A
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DOI：
10.1016/s0008-6363(02)00837-4
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发表时间：
2003-03-15
影响因子：
10.8
通讯作者：
Lang, F
中科院分区：
文献类型：
--
作者：
Boehmer, C;Wilhelm, V;Lang, F
血清和糖皮质激素诱导激酶 SGK1 及其亚型 SGK3 均在心脏组织中表达。 SGK1 的功能之一是泛素连接酶 Nedd4-2 的磷酸化和失活，这反过来又可以下调电压门控 Na+ 通道 SCN5A (hH1)。本研究旨在测试 SGK1 和 SGK3 在 SCN5A 调节中的作用。为此，将编码人Na+通道SCN5A的cRNA注射到非洲爪蟾卵母细胞中，有或没有编码野生型激酶SGK1、组成型活性激酶(S422D)SGK1、非活性形式(K127N)SGK1或野生型SGK3的cRNA。 SCN5A 电流通过野生型 SGK1 或 SGK3 或组成型活性 (S422D)SGK1 的共表达而激活。相反，失活突变体 (K127N)SGK1 显着降低了电流。此外，SGK3 的共表达显着改变了 SCN5A 门控，即它使激活阈值超极化，并使通道 50% 可用性所需的预电位去极化。 SCN5A 的 SGK 共有序列中丝氨酸突变为丙氨酸（(S483A)SCN5A 和 (S663A)SCN5A），引起门控特性的相反转变。目前的观察结果揭示了激酶 SGK1 和 SGK3 在调节心脏 Na+ 通道中的作用。由于 SGK1 被糖皮质激素、盐皮质激素和多种炎症介质上调，并且两种激酶均被胰岛素和 IGF1 激活，因此激酶可以介导这些激素和介质对心脏功能的影响。 (C) 2003 年欧洲心脏病学会。由 Elsevier Science B.V. 出版。保留所有权利。
The serum and glucocorticoid inducible kinase SGK1 and its isoform SGK3 are both expressed in cardiac tissue. One of the functions of SGK1 is the phosphorylation and inactivation of the ubiquitin ligase Nedd4-2, which in turn could be shown to downregulate the voltage-gated Na+ channel SCN5A (hH1). The present study has been performed to test for a role of SGK1 and SGK3 in the regulation of SCN5A. To this end cRNA encoding the human Na+ channel SCN5A was injected into Xenopus laevis oocytes with or without cRNA encoding the wild-type kinases SGK1, the constitutively active kinase (S422D)SGK1, the inactive form (K127N)SGK1 or the wild-type SGK3. SCN5A currents were activated by coexpression of either wild-type SGK1 or SGK3 or the constitutively active (S422D)SGK1. In contrast, the inactive mutant (K127N)SGK1 significantly decreased the currents. Moreover, coexpression of SGK3 significantly altered SCN5A gating, i.e. it hyperpolarized the activation threshold and depolarized the prepotential required for 50% availability of the channel. Opposite shifts of gating properties were elicited by mutation of serine to alanine ((S483A)SCN5A and (S663A)SCN5A) in the SGK consensus sequences of SCN5A. The present observations disclose a role of the kinases SGK1 and SGK3 in the regulation of cardiac Na+ channels. As SGK1 is upregulated by glucocorticoids, mineralocorticoids and a variety of inflammatory mediators and both kinases are activated by insulin and IGF1, the kinases could mediate effects of those hormones and mediators on cardiac function. (C) 2003 European Society of Cardiology. Published by Elsevier Science B.V. All rights reserved.