Conformational mechanisms of mGluR gating and regulation

总结/摘要 G蛋白偶联受体（GPCR）是最大的一类膜信号蛋白，对广泛的 一系列细胞外刺激通过G蛋白和抑制蛋白启动细胞内信号传导。最近的研究 提供了不同构象的GPCR结构的快照，并揭示了它们是非常 动态的构象动力学似乎是配体识别，激活和信号传导的中心。 膜受体已经进化到对细胞外基质的精确时空浓度分布做出响应， 配体。在神经系统中，神经递质受体遇到广泛的神经递质 浓度和时空分布。关键因素是突触间隙的细胞外体积小， 移除神经递质的泵和/或酶以及扩散。此外，神经递质受体 在突触前和突触后，以及突触外， 遇到局部释放的神经递质，在裂隙内短暂达到低毫摩尔水平， 从附近的突触溢出，达到较低的浓度。代谢型谷氨酸受体 （mGluRs）在兴奋性谷氨酸能突触的突触前和突触后，以及神经胶质细胞和 抑制性GABA能突触前神经末梢，这意味着它们被两种高局部激活 释放和溢出地点附近的浓度。各种mGluR可以在 突触前神经末梢，即使它们都耦合到相同的G蛋白。它们可以二聚化， 产生混合的或在某些情况下完全独特的性质和药理学特征。了解什么 每一种mGluR亚型都能开发出有效的药物来治疗它们所处的神经系统疾病。 我们需要了解它们是如何运作的，以及它们是如何被调节的。我们的目标是定义 设定和调节同源和异源mGluRs功能特性的分子机制， 突触并进行可用于筛查神经系统调制的测定。

SUMMARY/ABSTRACT G-protein–coupled receptors (GPCRs), the largest class of membrane signaling proteins, respond to a wide array of extracellular stimuli to initiate intracellular signaling via G proteins and arrestins. Recent studies have provided snapshots of GPCR structures in distinct conformations and revealed that they are extremely dynamic. The conformational dynamics appear to be central to ligand recognition, activation and signaling. Membrane receptors have evolved to respond to precise spatio-temporal concentration profiles of extracellular ligands. In the nervous system, neurotransmitter receptors encounter a wide range of neurotransmitter concentrations and spatio-temporal profiles. Key factors are the small extracellular volume of the synaptic cleft, pumps and/or enzymes that remove neurotransmitter, and diffusion. Additionally, neurotransmitter receptors can be localized within the synapse both pre- and postsynaptically, as well as extrasynaptically where they can encounter neurotransmitter released either locally, which briefly reaches low millimolar levels within the cleft, and spillover from nearby synapses, which reaches lower concentrations. Metabotropic glutamate receptors (mGluRs) are found pre- and postsynaptically at excitatory glutamatergic synapses, as well as on glia and at inhibitory GABAergic presynaptic nerve terminals, meaning that they are activated by both high local concentrations near the site of release and spillover. mGluRs of various kinds can be found together in presynaptic nerve terminals, even when they are all coupled to the same G protein. And they can dimerize, generating hybrid or in some cases totally unique properties and pharmacological profiles. To understand what each mGluR subtype does and develop effective drugs to treat the neurological disorders in which they are implicated, we need to understand how they function and how they are regulated. Our goal here is to define the molecular mechanisms that set and regulate the functional properties of homo- and heteromeric mGluRs at synapses and put into place assays that can be used to screen modulation in the nervous system.