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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Crucial role of a shared extracellular loop in apamin sensitivity and maintenance of pore shape of small- conductance calcium-activated potassium (SK) channels
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Crucial role of a shared extracellular loop in apamin sensitivity and maintenance of pore shape of small- conductance calcium-activated potassium (SK) channels

机译：共享的细胞外环在apapamin敏感性和维持小电导钙激活钾（SK）通道的孔形状中的关键作用

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摘要

Activation of small-conductance calcium (Ca~(2+))-dependent potassium (K_(Ca)2) channels (herein called "SK") produces membrane hy-perpolarization to regulate membrane excitability. Three subtypes (SK1-3) have been cloned and are distributed throughout the nervous system, smooth muscle, and heart. It is difficult to discern the physiological role of individual channel subtypes as most blockers or enhancers do not discriminate between subtypes. The archetypical blocker apamin displays some selectivity between SK channel subtypes, with SK2 being the most sensitive, followed by SK3 and then SK1. Sensitivity of SK1 is species specific, with the human isoform being blocked by the toxin, whereas the rat is not. Muta-- tion studies have identified residues within the outer pore that suggest apamin blocks by an allosteric mechanism. Apamin also uses a residue within the S3-S4 extracellular loop to produce a high-sensitivity block. We have identified that a 3-amino acid motif within this loop regulates the shape of the channel pore. This motif is required for binding and block by apamin, suggesting that a change in pore shape underlies allosteric block. This motif is absent in rat SK1, explaining why it is insensitive to block by apamin. The overlapping distribution of SK channel subtype expression suggests that native heteromeric channels may be common. We show that the S3-S4 loop of one subunit overlaps the outer pore of the adjacent subunit, with apamin interacting with both regions. This arrangement provides a unique binding site for each combination of SK subunits within a coassembled channel that may be targeted to produce blockers specific for heteromeric SK channels.
机译：小电导的钙（Ca〜（2+））依赖性钾（K_（Ca）2）通道（以下称为“ SK”）的激活产生膜超极化，从而调节膜的兴奋性。已克隆了三种亚型（SK1-3），它​​们分布于整个神经系统，平滑肌和心脏。由于大多数阻滞剂或增强剂不能区分亚型，因此很难辨别单个通道亚型的生理作用。原型阻滞剂apamin在SK通道亚型之间显示出一定的选择性，其中SK2最敏感，其次是SK3，然后是SK1。 SK1的敏感性是物种特异性的，人同工型被毒素阻断，而大鼠则没有。突变研究已发现外孔中的残留物，表明其通过变构机制阻断了甜菜碱的形成。 Apamin还使用S3-S4细胞外环内的残基来产生高敏感性阻滞。我们已经发现，在该环内的3-氨基酸基序调节通道孔的形状。该基序是必需的，以被木瓜蛋白酶结合和阻断，表明孔构型改变是变构阻断的基础。大鼠SK1中不存在该基序，这解释了为什么它不被Apapamin阻断敏感。 SK通道亚型表达的重叠分布表明，天然异源通道可能很常见。我们显示，一个亚基的S3-S4环与相邻亚基的外孔重叠，且与糊精相互作用的两个区域。这种布置为共同组装的通道内的SK亚基的每种组合提供了独特的结合位点，其可被靶向产生对异源SK通道特异的阻滞剂。

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