Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, Chonqing, China.
Department of Neurology, The Affiliated Hospital of Zunyi Medical University, Guizhou, China.
CNS Neurosci Ther. 2022 Jan;28(1):126-138. doi: 10.1111/cns.13746. Epub 2021 Oct 22.
It has been reported that the G-alpha interacting protein (GAIP) interacting protein, C terminus 1 (GIPC1/GIPC) engages in vesicular trafficking, receptor transport and expression, and endocytosis. However, its role in epilepsy is unclear. Therefore, in this study, we aimed to explore the role of GIPC1 in epilepsy and its possible underlying mechanism.
The expression patterns of GIPC1 in patients with temporal lobe epilepsy (TLE) and in mice with kainic acid (KA)-induced epilepsy were detected. Behavioral video monitoring and hippocampal local field potential (LFP) recordings were carried out to determine the role of GIPC1 in epileptogenesis after overexpression of GIPC1. Coimmunoprecipitation (Co-IP) assay and high-resolution immunofluorescence staining were conducted to investigate the relationship between GIPC1 and metabotropic glutamate receptor 7 (mGluR7). In addition, the expression of mGluR7 after overexpression of GIPC1 was measured, and behavioral video monitoring and LFP recordings after antagonism of mGluR7 were performed to explore the possible mechanism mediated by GIPC1.
GIPC1 was downregulated in the brain tissues of patients with TLE and mice with KA-induced epilepsy. After overexpression of GIPC1, prolonged latency period, decreased epileptic seizures and reduced seizure severity in behavioral analyses, and fewer and shorter abnormal brain discharges in LFP recordings of KA-induced epileptic mice were observed. The result of the Co-IP assay showed the interaction between GIPC1 and mGluR7, and the high-resolution immunofluorescence staining also showed the colocalization of these two proteins. Additionally, along with GIPC1 overexpression, the total and cell membrane expression levels of mGluR7 were also increased. And after antagonism of mGluR7, increased epileptic seizures and aggravated seizure severity in behavioral analyses and more and longer abnormal brain discharges in LFP recordings were observed.
GIPC1 regulates epileptogenesis by interacting with mGluR7 and increasing its expression.
已有报道称，G 蛋白α相互作用蛋白（GAIP）相互作用蛋白 C 端 1（GIPC1/GIPC）参与囊泡运输、受体转运和表达以及内吞作用。然而，其在癫痫中的作用尚不清楚。因此，本研究旨在探讨 GIPC1 在癫痫中的作用及其可能的潜在机制。
检测了颞叶癫痫（TLE）患者和海人酸（KA）诱导癫痫小鼠中 GIPC1 的表达模式。通过行为视频监测和海马局部场电位（LFP）记录，确定过表达 GIPC1 后 GIPC1 在癫痫发生中的作用。通过共免疫沉淀（Co-IP）测定和高分辨率免疫荧光染色，研究 GIPC1 与代谢型谷氨酸受体 7（mGluR7）之间的关系。此外，还测量了过表达 GIPC1 后 mGluR7 的表达，并在拮抗 mGluR7 后进行行为视频监测和 LFP 记录，以探讨 GIPC1 介导的可能机制。
GIPC1 在 TLE 患者和 KA 诱导癫痫小鼠的脑组织中表达下调。过表达 GIPC1 后，KA 诱导癫痫小鼠的行为分析潜伏期延长、癫痫发作减少、癫痫发作严重程度降低，LFP 记录中异常脑放电减少且持续时间缩短。Co-IP 测定结果显示 GIPC1 与 mGluR7 相互作用，高分辨率免疫荧光染色也显示这两种蛋白的共定位。此外，随着 GIPC1 的过表达，mGluR7 的总蛋白和细胞膜表达水平也增加。拮抗 mGluR7 后，行为分析中癫痫发作增加且严重程度加重，LFP 记录中异常脑放电增多且持续时间延长。
GIPC1 通过与 mGluR7 相互作用并增加其表达来调节癫痫发生。
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