GPRIN proteins and their effects on kainate receptor function

离子型谷氨酸受体是配体门控通道，对中枢神经系统中的神经元通讯至关重要；损害受体功能的突变会导致神经表型，包括严重的神经发育障碍。这些受体被分为三类，并根据它们的药理激动剂命名：α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic酸(AMPA)、N-甲基-D-天冬氨酸(N-甲基-D-天冬氨酸)和红藻氨酸(KA)。虽然AMPA和NMDA受体介导了脑中大部分快速兴奋性突触后电流，但KA受体(KAR)对突触后兴奋性的贡献局限于离散的突触，这些离子型谷氨酸受体似乎比其他两种类型具有更多不同的功能。有趣的是，与NMDA和AMPA受体功能不同，尽管KAR不属于G蛋白偶联受体家族(GPCRs)，但许多KAR功能是通过激活异源三聚体G蛋白以一种非规范的代谢性方式介导的。我们对KAR相互作用蛋白的鉴定和功能特性很感兴趣，最近我们发现了一种KAR相互作用蛋白，称为G蛋白调节的轴突生长诱导因子1(GPRIN1)。我们假设GPRIN1调节KAR电流的特定特征，如其缓慢的动力学。此外，GPRIN1可能参与神经元发育的KAR调节，并作为异源三聚体G蛋白复合体的伙伴发挥作用。为了阐明GPRIN和KARS之间的联系的作用，我们将在一个由两个分项目组成的方案中工作。首先，我们将剖析KARS和GPRIN家族成员之间相互作用的本质，并使用生化和基于细胞的分析来研究这种相互作用的功能后果。接下来，我们将研究影响这两种蛋白功能关联的生理条件，并探索功能GPRIN与内源性KAR功能的相关性。

The ionotropic glutamate receptors are ligand-gated channels of critical importance for neuronal communication in the central nervous system; mutations that impair receptor function cause neurological phenotypes that include severe neurodevelopmental disturbances. These receptors have been grouped into three categories and named according to their pharmacological agonists: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), N-methyl-D-aspartate (NMDA), and kainic acid (KA). While AMPA and NMDA receptors mediate most of the fast excitatory postsynaptic currents in the brain, the KA receptor (KAR) contribution to postsynaptic excitability is localised to discrete synapses, and these ionotropic glutamate receptors seem to serve more diverse functions than the other two types. Interestingly, unlike NMDA and AMPA receptor functions, many KAR functions are mediated by activation of heterotrimeric G proteins, in a non-canonical, metabotropic way, even though KARs do not belong to the G protein-coupled receptor family (GPCRs). We are interested in the identification and functional characterisation of KAR-interacting proteins, and we have recently identified a KAR-interacting protein known as G protein-regulated inducer of neurite outgrowth 1 (GPRIN1). We hypothesise that GPRIN1 modulates specific characteristics of KAR currents, such as their slow kinetics. Moreover, GPRIN1 may be involved in the KAR modulation of neuronal development and function as a partner in a complex with heterotrimeric G proteins. To elucidate the role of the association between GPRINs and KARs, we will work in a programme composed of two sub-projects. First, we will dissect the nature of the interaction between KARs and members of the GPRIN family and examine the functional consequences of this interaction using biochemical and cell-based assays. Next, we will investigate the physiological conditions that influence the functional association of these two proteins and also explore the relevance of functional GPRIN for endogenous KAR function.