Department of Biological Sciences, Indian Institute of Science Education and Research, Mohali, Knowledge City, 140306, Punjab, India.
Department of Biological Sciences, Indian Institute of Science Education and Research, Mohali, Knowledge City, 140306, Punjab, India
J Neurosci. 2018 Oct 3;38(40):8605-8620. doi: 10.1523/JNEUROSCI.0454-18.2018. Epub 2018 Aug 24.
Group I metabotropic glutamate receptors (mGluRs) function as modulators of neuronal physiology and they have also been implicated in various neuropsychiatric disorders. Trafficking of mGluRs plays important roles in controlling the precise localization of these receptors at specific region of the cell, as well as it regulates the activity of these receptors. Despite this obvious significance, we know very little about the cellular machineries that control the trafficking of these receptors in the CNS. Sorting nexin 1 (SNX1) has been shown to regulate the endosomal sorting of few cell surface receptors either to lysosomes where they are downregulated or back to the cell surface. Using "molecular replacement" approach in hippocampal neurons derived from mice of both sexes, we show here that SNX1 plays critical role in the trafficking of mGluR1, a member of the group I mGluR family. Overexpression of dominant-negative SNX1 or knockdown of endogenous SNX1 resulted in the rapid recycling of the receptor. Importantly, recycling via the rapid recycling route, did not allow the resensitization of the receptors. Our data suggest that both, N-terminal and C-terminal region of SNX1 play critical role in the normal trafficking of the receptor. In addition, we also show here that SNX1 regulates the trafficking of mGluR1 through the interaction with Hrs (hepatocyte growth factor-regulated tyrosine kinase substrate), a protein that has been implicated in both signaling and vesicular trafficking. Thus, these studies reveal a mechanistic role of SNX1 in the trafficking of group I mGluRs and its physiological implications. Group I mGluRs are activated by the neurotransmitter glutamate in the CNS, and play various important roles in the brain. Similar to many other receptors, trafficking plays crucial roles in controlling the precise localization as well as activity of these receptors. Despite this obvious significance very little is known about the cellular machineries that control the trafficking of these receptors. We demonstrate here, that SNX1 plays a critical role in the trafficking of mGluR1, a member of the group I mGluR family. SNX1-mediated trafficking is critical for the resensitization of the receptor. SNX1 controls the trafficking of the receptor through the interaction with another protein, Hrs. The results suggest a role for SNX1 in the regulation of group I mGluRs.
I 型代谢型谷氨酸受体（mGluRs）作为神经元生理学的调节剂发挥作用，它们也与各种神经精神疾病有关。mGluR 的运输在控制这些受体在细胞特定区域的精确定位以及调节这些受体的活性方面起着重要作用。尽管这一意义明显，但我们对控制中枢神经系统中这些受体运输的细胞机制知之甚少。分选连接蛋白 1（SNX1）已被证明可以调节少数细胞表面受体的内体分拣，要么将其分拣到溶酶体中使其下调，要么将其分拣回细胞表面。在这里，我们使用来自两性小鼠的海马神经元的“分子置换”方法表明，SNX1 在 I 型 mGluR 家族成员 mGluR1 的运输中发挥关键作用。显性负 SNX1 的过表达或内源性 SNX1 的敲低导致受体的快速再循环。重要的是，通过快速再循环途径的再循环不允许受体重新敏化。我们的数据表明，SNX1 的 N 端和 C 端区域都在受体的正常运输中发挥关键作用。此外，我们还在这里表明，SNX1 通过与 Hrs（肝细胞生长因子调节的酪氨酸激酶底物）相互作用来调节 mGluR1 的运输，该蛋白已被证明与信号转导和囊泡运输都有关。因此，这些研究揭示了 SNX1 在 I 型 mGluR 运输中的机制作用及其生理意义。I 型 mGluRs 在中枢神经系统中被神经递质谷氨酸激活，在大脑中发挥各种重要作用。与许多其他受体类似，运输在控制这些受体的精确定位以及活性方面起着至关重要的作用。尽管这一意义明显，但我们对控制这些受体运输的细胞机制知之甚少。在这里，我们证明 SNX1 在 I 型 mGluR 家族成员 mGluR1 的运输中发挥关键作用。SNX1 介导的运输对受体的再敏化至关重要。SNX1 通过与另一种蛋白质 Hrs 的相互作用来控制受体的运输。结果表明 SNX1 在 I 型 mGluR 的调节中起作用。
