Identifying molecules that modulate auxiliary factors of AMPA receptors

描述：认知、行为、神经回路的活动、突触可塑性和神经元存活与离子型谷氨酸受体(IGluRs)的配基门控离子通道的正常功能有关。AMPA型iGluRs(AMPA-Rs)参与哺乳动物脑内大部分兴奋性突触传递，其功能障碍涉及多种神经和精神疾病。例如，AMPA-R的阳性调节剂缓解了严重抑郁障碍(MDD)的症状，突触AMPA-R在阿尔茨海默病小鼠模型中减少，与AMPA-R结合的自身抗体导致拉斯穆森脑炎和边缘脑炎的子集。特别是，现有的针对AMPA-R的MDD药物具有局限性，需要机械上新的AMPA-R调节剂来治疗开发和了解疾病机制。AMPA-Rs是由？然后呢？亚单位。那个？亚基被称为GluA1-4，构成配体门控离子通道孔的四聚体核心，而？亚基有助于受体的功能调节，而不是孔结构的一部分。那个？亚基也被称为辅助因子，可以认为是自然界在进化过程中发展起来的一组内源性AMPA-Rs调节剂。辅助因子调节AMPA受体介导的突触后反应的大小和形状。从机制上讲，调节转运与改变突触上AMPA受体的数目和迁移率有关，而改变离子通道的门控动力学将直接改变膜去极化的时间进程。通过改变影响突触后电流的运输和门控参数，辅助亚单位影响重合检测和树突整合。最终，这种突触调节被认为会影响神经回路和行为的活动。因此，可以想象，干预AMPA-Rs的内源调节剂将具有强大的生理效应。然而，目前还不清楚是否会发生这种情况。IGluR亚基可能是调控配体门控离子通道功能的有效药物靶点。为了检验这一假设， 我们计划将HTS与我们开发的新的基于细胞的分析相结合，以筛选特定作用于AMPA-Rs辅助因子依赖调制的化合物。针对AMPA-Rs开发的常规药物侧重于毛孔形成？亚单位。如果从我们提出的筛选中发现新的探针，iGluR的辅助因子将成为药物开发的机械性新靶点。重要的是要注意这点？钾通道中的亚基已经成为药物靶点。新的AMPA-Rs内源性辅助因子不断被发现，提供了更广泛的分子靶点。每个辅助因子都有不同的表达模式，表明靶向药物将具有细胞类型的特异性作用。使用所提出的HTS筛选方法，通过与辅助亚单位相互作用来识别调节AMPA-R活性的化合物将为开发抗AMPA-R的新药，特别是针对MDD的新药提供范式转变。

DESCRIPTION: Cognition, behavior, activity of neural circuits, synaptic plasticity, and neuronal survival relate to proper functioning of ligand gated ion channels of the ionotropic glutamate receptors (iGluRs). AMPA-type iGluRs (AMPA-Rs) contribute to the majority of excitatory synaptic transmission in mammalian brain and their dysfunction involves a variety of neurological and psychiatric disorders. For example, positive modulators of AMPA-Rs alleviate major depression disorder (MDD) symptoms, synaptic AMPA-Rs are reduced in mouse models of Alzheimer's disease, and auto-antibodies that bind to AMPA-Rs cause Rasmussen's encephalitis and a subset of limbic encephalitis. In particular, existing drugs for MDD targeting AMPA-Rs have limitations and mechanistically novel AMPA-R modulators are needed for therapeutic development and understanding disease mechanism. AMPA-Rs are protein complexes made of ? and ? subunits. The ? subunits are known as GluA1-4 and construct the tetrameric core of the ligand gated ion channel pore, whereas ? subunits contribute to functional modulation of the receptors without being part of the pore structure. The ? subunits are also known as the auxiliary factors and may be regarded as a set of endogenous modulators of AMPA-Rs developed by nature during evolution. Auxiliary factors modulate the magnitude and shape of postsynaptic responses mediated by AMPA-Rs. Mechanistically, modulating trafficking relates to changing the number and mobility of AMPA-Rs at synapses, whereas altering the gating kinetics of the ion channel will directly modify the time course of membrane depolarization. By changing trafficking and gating parameters influencing postsynaptic currents, auxiliary subunits impact coincident detection and dendritic integration. Ultimately such synaptic modulation is believed to affect the activity of neural circuits and behavior. It is thus conceivable that intervening with endogenous modulators of AMPA-Rs would have strong physiological effects. It is unclear, however, whether ? subunits of iGluR would be effective drug targets for manipulating ligand gated ion channel function. To test this hypothesis, we plan to combine HTS with new cell based assays we developed in order to screen for chemical compounds that specifically act on auxiliary factor dependent modulation of AMPA-Rs. Conventional drugs developed against AMPA-Rs focus on pore forming ? subunits. If new probes are identified from our proposed screening, auxiliary factors of iGluR will become a mechanistically new target for drug development. It is important to note that ? subunits in potassium channels are already established drug targets. New endogenous auxiliary factors of AMPA-Rs are continuously being identified, providing broader spectrum of molecular targets. Each auxiliary factor has distinct expression patters, indicating that targeted drugs will have cel-type specific effects. Using the proposed HTS screening approach, the identification of compounds that modulate AMPA-R activity through interaction with the auxiliary subunits will provide a paradigm shift in developing new drugs against AMPA-Rs, in particular for MDD.