Role of the Ion Channel Extracellular Collar in AMPA Receptor Gating.
Role of the Ion Channel Extracellular Collar in AMPA Receptor Gating.
复制标题
DOI：
10.1038/s41598-017-01146-z
复制
发表时间：
2017-04-21
影响因子：
4.6
通讯作者：
Sobolevsky AI
中科院分区：
文献类型：
--
作者：
Yelshanskaya MV;Mesbahi-Vasey S;Kurnikova MG;Sobolevsky AI
AMPA亚型离子型谷氨酸受体介导快速兴奋性神经传递，并与许多神经系统疾病有关。通过AMPA受体通道的离子电流可以通过受体蛋白上的不同位点进行变构调节。我们使用定点突变和膜片钳记录来探测离子通道的细胞外领，非竞争性变构抑制剂的结合区域。我们发现在AMPA受体门控的这一区域引入突变的位置和取代依赖性效应。突变的结果表明，跨膜结构域M1，M3和M4，这有助于离子通道细胞外领，在门控过程中发生显着的相对位移。我们使用分子动力学模拟来预测AMPA受体的开放态结构，并合理化诱变的结果。我们的结论是，离子通道细胞外领门控中起着独特的作用，并代表了一个枢纽强大的变构调制AMPA受体功能，可用于开发新的治疗方法。
AMPA subtype ionotropic glutamate receptors mediate fast excitatory neurotransmission and are implicated in numerous neurological diseases. Ionic currents through AMPA receptor channels can be allosterically regulated via different sites on the receptor protein. We used site-directed mutagenesis and patch-clamp recordings to probe the ion channel extracellular collar, the binding region for noncompetitive allosteric inhibitors. We found position and substitution-dependent effects for introduced mutations at this region on AMPA receptor gating. The results of mutagenesis suggested that the transmembrane domains M1, M3 and M4, which contribute to the ion channel extracellular collar, undergo significant relative displacement during gating. We used molecular dynamics simulations to predict an AMPA receptor open state structure and rationalize the results of mutagenesis. We conclude that the ion channel extracellular collar plays a distinct role in gating and represents a hub for powerful allosteric modulation of AMPA receptor function that can be used for developing novel therapeutics.