Interface Interactions Modulating Desensitization of the Kainate-Selective Ionotropic Glutamate Receptor Subunit GluR6
Interface Interactions Modulating Desensitization of the Kainate-Selective Ionotropic Glutamate Receptor Subunit GluR6
复制标题
界面相互作用调节红藻酸盐选择性离子型谷氨酸受体亚基 GluR6 的脱敏
作者：
Yihong Zhang;N. Nayeem;M. Nanao;T. Green
来自AMPA和红藻氨酸盐亚家族的离子型谷氨酸盐受体共享许多功能和结构特征，但尚不清楚这种相似性是否延伸到受体脱敏的分子机制。目前AMPA受体脱敏的模型涉及亚单位激动剂结合结构域之间形成的二聚体的重排。这一点的关键证据来自单点突变体（从亮氨酸到酪氨酸），该突变体消除了脱敏作用，并且被证明可以稳定结合结构域二聚体。然而，红藻氨酸受体的脱敏似乎在几个关键方面不同于AMPA受体。虽然AMPA受体门控和脱敏的动力学与从两个二聚体形成的通道一致，但在红藻氨酸受体中尚未发现二聚体功能参与的类似证据。此外，尽管AMPA亚基中的非脱敏酪氨酸的同源物也是野生型红藻氨酸亚基中的酪氨酸，但这些受体迅速且完全脱敏。使用诱变的基础上的晶体结构的谷氨酸受体亚基GluR6 S1S2域与domoate复合物，我们确定了四个残基邻近这个酪氨酸之间的AMPA和红藻氨酸亚基不同，并有助于这些受体的不同脱敏动力学。在这些网站的突变的影响的详细分析证实，事实上有一个共同的一般机制脱敏在非NMDA受体，依赖于结合域二聚体界面的稳定性，并揭示了潜在的激动剂特异性脱敏途径的存在。
Ionotropic glutamate receptors from the AMPA and kainate subfamilies share many functional and structural features, but it is unclear whether this similarity extends to the molecular mechanisms underlying receptor desensitization. The current model for desensitization in AMPA receptors involves the rearrangement of dimers formed between subunit agonist binding domains. Key evidence for this has come from a single point mutant (from leucine to tyrosine) that abolished desensitization and that was shown to stabilize the binding domain dimer. However, the desensitization of kainate receptors appears to differ from that of AMPA receptors in several key respects. Although the kinetics of AMPA receptor gating and desensitization are consistent with channels formed from two dimers, similar evidence for the functional involvement of dimers has not been found in kainate receptors. Furthermore, despite the homolog of the nondesensitizing tyrosine in AMPA subunits also being a tyrosine in wild-type kainate subunits, these receptors desensitize rapidly and completely. Using mutagenesis based on the crystal structure of the glutamate receptor subunit GluR6 S1S2 domain in complex with domoate, we identified four residues neighboring this tyrosine that differ between AMPA and kainate subunits and that contribute to the different desensitization kinetics of these receptors. Detailed analysis of the effects of mutations at these sites confirms that there is in fact a common general mechanism for desensitization in non-NMDA receptors, dependent on the stability of the binding domain dimer interface, and reveals the existence of potential agonist-specific desensitization pathways.
影响因子：
56.9
作者：
Rosenmund, C;Stern-Bach, Y;Stevens, CF
通讯作者：
Stevens, CF