A dipeptidyl aminopeptidase-like protein remodels gating charge dynamics in Kv4.2 channels
A dipeptidyl aminopeptidase-like protein remodels gating charge dynamics in Kv4.2 channels
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DOI：
10.1085/jgp.200609668
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发表时间：
2006-12-01
影响因子：
3.8
通讯作者：
Covarrubias, Manuel
中科院分区：
文献类型：
--
作者：
Dougherty, Kevin;Covarrubias, Manuel
二肽氨肽酶样蛋白 (DPLP) 与 Kv4 通道相互作用，从而诱导激活和失活门控的深刻重塑。 DPLP 是神经元 Kv4 通道复合物的组成部分，最近的观察表明这些蛋白质的单个跨膜片段具有关键的功能作用（Zagha, E., A. Ozaita, S. Y. Chang, M. S. Nadal, U. Lin, M. J. Saganich, T. McCormack, K. O. Akinsanya, S. Y. Qi, and B. Rudy. 2005. J. 生物。化学。 280：18853-18861）。然而，潜在的作用机制尚不清楚。我们假设 Kv4.2 通道和大脑中发现的 DPLP (DPPX-S) 之间的独特相互作用可能会重塑通道的电压传感域。为了检验这一假设，我们实施了一个强大的实验系统来测量 Kv4.2 门控电流并研究在不存在和存在 DPPX-S 的情况下的门控电荷动态。结果表明，Kv4.2 和 DPPX-S 的共表达会导致门控电荷-电压 (Q-V) 关系发生 26 mV 的平行移动。这种转变与门控电荷在较宽的相关膜电位范围内更快的向外运动以及复极化时加速的门控电荷返回有关。与此形成鲜明对比的是，DPPX-S 对 Shaker B Kv 通道的门控电荷运动没有影响。我们认为 DPPX-S 会破坏电压依赖性激活途径中的静息态和中间态，从而促进向外的门控电荷运动。门控电荷动力学的重塑可能涉及 DPPX-S 跨膜片段与 Kv4.2 通道的电压传感和孔域的特定蛋白质-蛋白质相互作用。这种机制可能决定神经元 Kv4 通道在膜电位阈下范围内的快速运行特征。
Dipeptidyl aminopeptidase-like proteins (DPLPs) interact with Kv4 channels and thereby induce a profound remodeling of activation and inactivation gating. DPLPs are constitutive components of the neuronal Kv4 channel complex, and recent observations have suggested the critical functional role of the single transmembrane segment of these proteins (Zagha, E., A. Ozaita, S. Y. Chang, M. S. Nadal, U. Lin, M. J. Saganich, T. McCormack, K. O. Akinsanya, S. Y. Qi, and B. Rudy. 2005. J. Biol. Chem. 280: 18853-18861). However, the underlying mechanism of action is unknown. We hypothesized that a unique interaction between the Kv4.2 channel and a DPLP found in brain (DPPX-S) may remodel the channel's voltage-sensing domain. To test this hypothesis, we implemented a robust experimental system to measure Kv4.2 gating currents and study gating charge dynamics in the absence and presence of DPPX-S. The results demonstrated that coexpression of Kv4.2 and DPPX-S causes a-26 mV parallel shift in the gating charge-voltage (Q-V) relationship. This shift is associated with faster outward movements of the gating charge over a broad range of relevant membrane potentials and accelerated gating charge return upon repolarization. In sharp contrast, DPPX-S had no effect on gating charge movements of the Shaker B Kv channel. We propose that DPPX-S destabilizes resting and intermediate states in the voltage-dependent activation pathway, which promotes the outward gating charge movement. The remodeling of gating charge dynamics may involve specific protein-protein interactions of the DPPX-S's transmembrane segment with the voltage-sensing and pore domains of the Kv4.2 channel. This mechanism may determine the characteristic fast operation of neuronal Kv4 channels in the subthreshold range of membrane potentials.