Molecular determinants of positive allosteric modulation of the human metabotropic glutamate receptor 2
Molecular determinants of positive allosteric modulation of the human metabotropic glutamate receptor 2
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DOI：
10.1111/bph.13065
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发表时间：
2015-05-01
影响因子：
7.3
通讯作者：
Tresadern, G.
中科院分区：
文献类型：
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作者：
Farinha, A.;Lavreysen, H.;Tresadern, G.
背景和目的代谢型谷氨酸受体 2 (mGlu(2)) 的激活会减少大脑区域中的谷氨酸传递，在这些区域中，过度的兴奋性信号传导与焦虑和精神分裂症等疾病有关。正变构调节剂 (PAM) 可以微调这些受体的功能，并作为一种新型治疗方法进行研究。使用大量突变型人类 mGlu(2) 受体来研究对该受体的正变构调节至关重要的分子决定因素。实验方法采用定点诱变、结合和功能测定来鉴定对九种 PAM 活性重要的氨基酸。放射性配体结合和诱变研究的数据用于计算对接，以基于 mGlu(1) 受体的最新结构来预测 mGlu(2) 受体模型的结合模式。 主要结果 TM3（R635、L639、F643）、TM5（L732）和 TM6（W773、F776）中的新氨基酸首次被鉴定为在 mGlu(2) 受体的活性中发挥重要作用。 mGlu(2) PAM。结论和意义 这项广泛的研究进一步加深了我们对 mGlu(2) 受体正变构调节的理解，并有助于改进 mGlu(2) PAM 的未来设计。
Background and PurposeThe activation of the metabotropic glutamate receptor 2 (mGlu(2)) reduces glutamatergic transmission in brain regions where excess excitatory signalling is implicated in disorders such as anxiety and schizophrenia. Positive allosteric modulators (PAMs) can provide a fine-tuned potentiation of these receptors' function and are being investigated as a novel therapeutic approach. An extensive set of mutant human mGlu(2) receptors were used to investigate the molecular determinants that are important for positive allosteric modulation at this receptor.Experimental ApproachSite-directed mutagenesis, binding and functional assays were employed to identify amino acids important for the activity of nine PAMs. The data from the radioligand binding and mutagenesis studies were used with computational docking to predict a binding mode at an mGlu(2) receptor model based on the recent structure of the mGlu(1) receptor.Key ResultsNew amino acids in TM3 (R635, L639, F643), TM5 (L732) and TM6 (W773, F776) were identified for the first time as playing an important role in the activity of mGlu(2) PAMs.Conclusions and ImplicationsThis extensive study furthers our understanding of positive allosteric modulation of the mGlu(2) receptor and can contribute to improved future design of mGlu(2) PAMs.