SMITten for KCNQ Channels.
SMITten for KCNQ Channels.
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DOI：
10.1016/j.bpj.2017.06.056
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发表时间：
2017-08
影响因子：
3.4
通讯作者：
A. Tzingounis
中科院分区：
文献类型：
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作者：
A. Tzingounis
在过去的二十年里，KCNQ钾通道家族(KCNQ1-5)的成员已经成为心脏和神经元兴奋性的关键调节因子(1，2)。KCNQ1通道是心脏慢钾电流Iks(1)的分子决定因素，KCNQ1通道是心脏动作电位复极的部分原因。KCNQ1通道的功能缺失变异导致罕见的心脏疾病，长QT综合征，以及功能获得变异导致心房颤动。相反，KCNQ2/3通道参与神经元活动。这些通道是M电流的分子决定因素，M电流是一种电压激活的神经元钾电流，表现出缓慢的激活-去激活动力学和无失活(2)。KCNQ2/3通道部分设定了轴突起始段的静息膜电位，这是神经元动作电位产生的部位(2)。此外，KCNQ2/3通道有助于短脉冲或高频放电后的中慢后超极化，从而防止神经元过度放电(2，3)。在严重的新生儿和婴儿癫痫脑病患者中，越来越多的功能缺失和功能获得变异(主要是在KCNQ2中，在KCNQ3中的程度较小)的报道进一步突显了这些渠道的重要性。KCNQ1和KCNQ2/3通道在生理和疾病中的关键作用引起了人们对了解它们的特性的极大兴趣。现在公认的是，KCNQ通道需要磷脂磷脂酰肌醇4，5-二磷酸(PIP2)才能发挥作用(1)。PIP2通过增加通道开放的概率和加强电压传感器和KCNQ孔之间的耦合来影响KCNQ1-3通道的活动。除了受PIP2的调节外，一些研究表明KCNQ1通道的活性还受一系列单一的跨膜蛋白的控制，包括KCNE1-3(1)。最近，肌醇转运体SMIT1和SMIT2被添加到与KCNQ1-3通道相互作用的蛋白质的万神殿中(4)。SMIT1和SMIT2是共同的载体，它们利用钠离子的下坡梯度将肌醇共同运输到细胞内。肌醇是一种渗透压物质，是PIP2的前体。在早期的一项研究中，Neverisky和Abbott(4)发现SMIT1和SMIT2与KCNQ1-3通道物理上相互作用，并相互调节它们的活动。对于KCNQ2/3通道，这种相互作用被认为是功能上的间接作用，与SMIT1/2
Over the last two decades, members of the KCNQ channel family of potassium channels (KCNQ1–5) have emerged as critical regulators of cardiac and neuronal excitability (1, 2). KCNQ1 channels are the molecular determinants of the cardiac slow potassium current, IKS (1), which is partly responsible for the repolarization of the cardiac action potential. Loss-offunction variants of KCNQ1 channels lead to a rare heart condition, long QT syndrome, and gain-of-function variants lead to atrial fibrillation. In contrast, KCNQ2/3 channels are involved in neuronal activity. These channels are the molecular determinants of the M-current, a voltage-activated neuronal potassium current that exhibits slow activation-deactivation kinetics and no inactivation (2). KCNQ2/3 channels partially set the resting membrane potential of the axon initial segment, the site of action potential generation in neurons (2). Additionally, KCNQ2/3 channels contribute to the medium and slow afterhyperpolarization that follows a short burst or high frequency train of spiking activity, thus preventing excessive neuronal firing (2, 3). Further highlighting the importance of these channels, a growing number of lossand gain-of-function variants (primarily in KCNQ2 and to a smaller extent in KCNQ3) have been reported in patients with severe neonatal and infantile epileptic encephalopathy. The critical roles of KCNQ1 and KCNQ2/3 channels in physiology and disease have generated great interest toward understanding their properties. It is now well accepted that KCNQ channels require the presence of phospholipid phosphatidylinositol 4, 5-bisphosphate (PIP2) to function (1). PIP2 exerts its effects on KCNQ1–3 channel activity by increasing the probability of channel opening and by strengthening the coupling between the voltage-sensor and the KCNQ pore. In addition to being regulated by PIP2, several studies have shown that KCNQ1 channel activity is controlled by a series of single transmembrane proteins, including KCNE1–3 (1).More recently, the myo-inositol transporters SMIT1 and SMIT2 have been added to the pantheon of proteins that interact with KCNQ1–3 channels (4). SMIT1 and SMIT2 are symport carriers that use the downhill gradient of sodium ions to cotransport myoinositol into cells. Myo-inositol is an osmolyte and a precursor to PIP2. In an earlier study, Neverisky and Abbott (4) found that SMIT1 and SMIT2 physically interact with KCNQ1–3 channels and reciprocally regulate their activity. For KCNQ2/3 channels, this interaction was thought to be functionally indirect, with SMIT1/2