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星形胶质细胞的NHERF-1通过抑制TREK-1的表面表达增加癫痫易感性。

Astrocytic NHERF-1 Increases Seizure Susceptibility by Inhibiting Surface Expression of TREK-1.

作者信息

Bae Yeonju, Lee Soomin, Kim Ajung, Lee Shinae, Kim Seong-Seop, Park Sunyoung, Noh Junyeol, Ryoo Kanghyun, Yi Gwan-Su, Park Jae-Yong, Hwang Eun Mi

机构信息

Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea.

School of Biosystems and Biomedical Sciences, College of Health Sciences, Korea University, Seoul, Republic of Korea.

出版信息

Glia. 2025 Apr;73(4):720-736. doi: 10.1002/glia.24644. Epub 2024 Nov 14.

DOI:10.1002/glia.24644
PMID:39543986
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11845839/
Abstract

Mature hippocampal astrocytes exhibit a linear current-to-voltage (I-V) K membrane conductance called passive conductance. It is estimated to enable astrocytes to keep potassium homeostasis in the brain. We previously reported that the TWIK-1/TREK-1 heterodimeric channels are crucial for astrocytic passive conductance. However, the regulatory mechanism of these channels by other binding proteins remains elusive. Here, we identified Na+/H+ exchange regulator-1 (NHERF-1), a protein highly expressed in astrocytes, as a novel interaction partner for these channels. NHERF-1 endogenously bound to TWIK-1/TREK-1 in hippocampal cultured astrocytes. When NHERF-1 is overexpressed or silenced, surface expression and activity of TWIK-1/TREK-1 heterodimeric channels are inhibited or enhanced, respectively. Furthermore, we confirmed that reduced astrocytic passive conductance by NHERF-1 overexpressing in the hippocampus increases kainic acid (KA)-induced seizure sensitivity. Taken together, these results suggest that NHERF-1 is a key regulator of TWIK-1/TREK-1 heterodimeric channels in astrocytes and suppression of TREK-1 surface expression by NHERF-1 increases KA-induced seizure susceptibility via reduction of astrocytic passive conductance.

摘要

成熟的海马星形胶质细胞表现出一种称为被动电导的线性电流-电压（I-V）钾膜电导。据估计，它能使星形胶质细胞维持大脑中的钾稳态。我们之前报道过，TWIK-1/TREK-1异源二聚体通道对星形胶质细胞的被动电导至关重要。然而，这些通道受其他结合蛋白的调控机制仍不清楚。在这里，我们鉴定出钠/氢交换调节因子-1（NHERF-1），一种在星形胶质细胞中高表达的蛋白质，作为这些通道的新型相互作用伙伴。NHERF-1在海马培养的星形胶质细胞中与TWIK-1/TREK-1内源性结合。当NHERF-1过表达或沉默时，TWIK-1/TREK-1异源二聚体通道的表面表达和活性分别受到抑制或增强。此外，我们证实，海马中NHERF-1过表达导致星形胶质细胞被动电导降低，增加了红藻氨酸（KA）诱导的癫痫敏感性。综上所述，这些结果表明NHERF-1是星形胶质细胞中TWIK-1/TREK-1异源二聚体通道的关键调节因子，NHERF-1对TREK-1表面表达的抑制通过降低星形胶质细胞的被动电导增加了KA诱导的癫痫易感性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b20f/11845839/6f6b0b35d660/GLIA-73-720-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b20f/11845839/90f27c9cd58e/GLIA-73-720-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b20f/11845839/80949e927b21/GLIA-73-720-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b20f/11845839/c14dc81af23a/GLIA-73-720-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b20f/11845839/f20e9be89aec/GLIA-73-720-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b20f/11845839/56edbdd617f6/GLIA-73-720-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b20f/11845839/7f44c60880b4/GLIA-73-720-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b20f/11845839/16e7818f3109/GLIA-73-720-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b20f/11845839/6f6b0b35d660/GLIA-73-720-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b20f/11845839/90f27c9cd58e/GLIA-73-720-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b20f/11845839/80949e927b21/GLIA-73-720-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b20f/11845839/c14dc81af23a/GLIA-73-720-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b20f/11845839/f20e9be89aec/GLIA-73-720-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b20f/11845839/56edbdd617f6/GLIA-73-720-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b20f/11845839/7f44c60880b4/GLIA-73-720-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b20f/11845839/16e7818f3109/GLIA-73-720-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b20f/11845839/6f6b0b35d660/GLIA-73-720-g006.jpg

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