Nav channel mechanosensitivity: Activation and inactivation accelerate reversibly with stretch
Nav channel mechanosensitivity: Activation and inactivation accelerate reversibly with stretch
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DOI：
10.1529/biophysj.106.101246
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发表时间：
2007-08-01
影响因子：
3.4
通讯作者：
Juranka, Peter F.
中科院分区：
文献类型：
--
作者：
Morris, Catherine E.;Juranka, Peter F.
电压门控钠通道(NAV)受许多双分子层机械两亲分子的调制，但它们是否像其他电压门控通道(Kv、Hcn、Cav)一样，对物理双分子层变形做出反应尚不清楚。我们在卵母细胞中表达了人心脏NaV1.5孔α亚单位(与αNav1.4不同，αNaV1.5表现出正常的动力学)，并在细胞附着的斑块中测量了微小的宏观电流。用吸管压力可逆性牵张，比较牵张前、牵张中、牵张后i-Na(T)的变化。在所有电压下，Stretch以剂量依赖的方式加速了i-Na(T)的时间进程。膜曲征象与此无关。典型的拉伸刺激可逆地加速激活和失活，其速度类似于1.4倍；I-Na(T)峰值的归一化后的时间尺度(类似于1.30-1.85倍)导致拉伸/非拉伸轨迹的完全重叠。显然，NAV1.5激活路径(如KV1)中限速外向电压传感器的运动随着拉伸而加速。即使在激活饱和的情况下，也会发生拉伸加速失活，因此独立拉伸调节的失活转变也是一种可能性。由于NAV1.5通道-拉伸调制既可靠又可逆，所需的拉伸刺激不会比通常激活假定的机械传感器通道(例如，拉伸激活的基于TRPC1的电流)的强度更大，NAV通道加入了假定的机械传感器的行列。值得注意的是，在接近激活阈值的电压下，适度拉伸使I-Na峰值幅度增加了1.5倍。确定伸展调节的NAV电流是否有助于心律失常、Cajal间质细胞的机械感觉反应、触摸感受器反应、神经病变(即机械超敏)和/或正常的痛觉感受将是重要的。
Voltage-gated sodium channels (Nav) are modulated by many bilayer mechanical amphiphiles, but whether, like other voltage-gated channels (Kv, HCN, Cav), they respond to physical bilayer deformations is unknown. We expressed human heart Nav1.5 pore alpha-subunit in oocytes (where, unlike alpha Nav1.4, alpha Nav1.5 exhibits normal kinetics) and measured small macroscopic currents in cell-attached patches. Pipette pressure was used to reversibly stretch the membrane for comparison of I-Na(t) before, during, and after stretch. At all voltages, and in a dose-dependent fashion, stretch accelerated the I-Na(t) time course. The sign of membrane curvature was not relevant. Typical stretch stimuli reversibly accelerated both activation and inactivation by similar to 1.4-fold; normalization of peak I-Na(t) followed by temporal scaling (similar to 1.30- to 1.85-fold) resulted in full overlap of the stretch/no-stretch traces. Evidently the rate-limiting outward voltage sensor motion in the Nav1.5 activation path (as in Kv1) accelerated with stretch. Stretch-accelerated inactivation occurred even with activation saturated, so an independently stretch-modulated inactivation transition is also a possibility. Since Nav1.5 channel-stretch modulation was both reliable and reversible, and required stretch stimuli no more intense than what typically activates putative mechanotransducer channels (e. g., stretch-activated TRPC1-based currents), Nav channels join the ranks of putative mechanotransducers. It is noteworthy that at voltages near the activation threshold, moderate stretch increased the peak I-Na amplitude similar to 1.5-fold. It will be important to determine whether stretchmodulated Nav current contributes to cardiac arrhythmias, to mechanosensory responses in interstitial cells of Cajal, to touch receptor responses, and to neuropathic (i. e., hypermechanosensitive) and/or normal pain reception.