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

• Published in: Glia
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: 14-11-2024
• ISSN: 0894-1491; 1098-1136; 1098-1136
• DOI: 10.1002/glia.24644

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.