The C-Terminal PDZ-Binding Motif in the Kv1.5 Potassium Channel Governs its Modulation by the Na+/H+ Exchanger Regulatory Factor 2
The C-Terminal PDZ-Binding Motif in the Kv1.5 Potassium Channel Governs its Modulation by the Na+/H+ Exchanger Regulatory Factor 2
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DOI：
10.1159/000204077
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发表时间：
2009-01-01
影响因子：
--
通讯作者：
Lang, Florian
中科院分区：
文献类型：
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作者：
Laufer, Joerg;Boehmer, Christoph;Lang, Florian
Kv1.5 属于电压门控钾 (Kv) 通道家族，包含 N 端和 C 端 PDZ 结合基序，可能被支架蛋白 NHERF1 和 NHERF2 上的 PDZ 结构域识别。非洲爪蟾卵母细胞的表达研究表明，NHERF1 和 NHERF2 激活 Kv1.5，这种效应需要 Kv1.5 上的 C 端 PDZ 结合基序。根据电生理学和免疫测定的结果，NHERF2 增强 Kv1.5 活性和细胞表面表达。 Brefeldin A 实验证明，NHERF2 通过减少通道内化来提高质膜上的 Kv1.5 丰度。 Kv1.5 受到血清和糖皮质激素诱导激酶 SGK1 的刺激，SGK1 是一种已知与 NHERF2 的第二个 PDZ 结构域相互作用的激酶。本研究旨在确定 SGK1 和 NHERF2 是否协同作用以增加 Kv1.5 电流。 NHERF2 的表达增强了 SGK1 介导的 Kv1.5 激活，而 NHERF2 中第二个 PDZ 结构域的缺失会显着减弱这种激活。通过评估 NHERF 对 Kv1.3 的影响来验证观察到的效果的特异性，Kv1.3 是一种已知的 SGK1 靶标，包含内部 PDZ 结合基序。总之，我们的结果表明 NHERF 可能部分通过控制 Kv1.5 表面丰度和将信号转导分子聚集到通道来参与电兴奋性的调节。版权所有 (C) 2009 S. Karger AG，巴塞尔
Kv1.5 belongs to the family of voltage-gated potassium (Kv) channels and contains a N- and a C-terminal PDZ-binding motif that might be recognized by PDZ domains on the scaffold proteins NHERF1 and NHERF2. Expression studies in Xenopus oocytes demonstrated that NHERF1 and NHERF2 activate Kv1.5, an effect requiring the C-terminal PDZ-binding motif on Kv1.5. NHERF2 enhances Kv1.5 activity and cell surface expression as determined by electrophysiology and immunoassays. NHERF2 elevates Kv1.5 abundance at the plasma membrane by decreasing channel internalization as proven by Brefeldin A experiments. Kv1.5 is stimulated by the serum and glucocorticoid inducible kinase SGK1, a kinase known to interact with the second PDZ domain of NHERF2. This study aims to identify if SGK1 and NHERF2 synergize to increase Kv1.5 currents. Expression of NHERF2 potentiated SGK1-mediated Kv1.5 activation, which was significantly attenuated by deletion of the second PDZ domain in NHERF2. Specificity of observed effects was verified by evaluating the influence of NHERFs on Kv1.3, a known SGK1 target that contains an internal PDZ binding motif. In summary, our results suggest that NHERFs might participate in the regulation of electrical excitability in part by controlling Kv1.5 surface abundance and by clustering signal transduction molecules to the channel. Copyright (C) 2009 S. Karger AG, Basel