NHERF-1 regulating surface expression of K2P channels in astrocytes

Abstract

Hallmarks of astrocytes include a high resting $K^+$ conductance and a linear current(I)-voltage(V) relationship called passive conductance. The passive conductance is an im-portant driving force for the extracellular ion and neurotransmitter homeostatic function of astrocytes. Recently, the molecular identity of this unique property of astrocytes was identified to be TREK-1/TWIK-1 heterodimers. However, the regulatory mechanism of these channels still remains obscure. Using bioinformatics, the possible regulatory proteins were listed and $Na^+/H^+$ exchanger regulatory factor-1 (NHERF-1) was selected as a novel candidate TWIK-1/TREK-1 heterodimer regulatory protein. NHERF-1 only interacts with the N-terminus region of TREK-1 and the PDZ-domain of NHERF-1 mediates this interaction. When NHERF-1 was overexpressed in cultured astrocytes, TREK-1/TWIK-1 mediated whole cell K+ currents and surface TREK-1/TWIK-1 levels were significantly decreased. On the other hand, knockdown of NHERF-1 in astrocytes using shRNA significantly increased whole cell K+ currents and surface expression of TREK-1/TWIK-1. Taken together, this study reports NHERF-1 regulation of TREK-1/TWIK-1 expression level in astrocytes.