RT Journal Article
SR Electronic
T1 Phosphatidylserine controls synaptic targeting and membrane stability of ASIC1a
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.09.29.509830
DO 10.1101/2022.09.29.509830
A1 Di-Shi Liu
A1 Xing-Lei Song
A1 Ming-Gang Liu
A1 Jianfei Lu
A1 Yu Huang
A1 Jaepyo Jeon
A1 Guofen Ma
A1 Yong Li
A1 Lucas Pozzo-Miller
A1 Michael X. Zhu
A1 Tian-Le Xu
YR 2022
UL http://biorxiv.org/content/early/2022/09/30/2022.09.29.509830.abstract
AB Phospholipid-protein interaction is highly specialized at the membranous nanodomains and critical for membrane receptor signaling. Calcium-permeable acid-sensing ion channel isoform 1a (ASIC1a) is a major neuronal proton sensor that contributes to synaptic plasticity. The functional outcome of ASIC1a is dependent on its surface targeting in synaptic subdomains; however, the lipid environment for ASIC1a and its role in channel targeting remain poorly understood. Here, we report that anionic phosphatidylserine (PS) is enriched in dendritic spines during neurodevelopment and it directly binds to ASIC1a through an electrostatic interaction with a di-arginine motif at ASIC1a C-terminus. PS regulates the membrane targeting and function of ASIC1a, which are both strongly suppressed by inhibition of PS synthesis. In cortical neuron dendrites, both PS and ASIC1a are predominately localized to peri-synaptic sites of spine heads, surrounding instead of overlapping with postsynaptic markers, PSD-95 and GluN1. Uncoupling the interaction between PS and ASIC1a by changing the charges to neutral or acidic at the di-arginine PS-binding motif, or applying a membrane penetrating competing peptide, caused mistargeting of ASIC1a at the synaptic sites, an overall increase in internalization and/or cytoplasmic accumulation of ASIC1a, and a decrease in its channel function. Together, our results provide novel insights on lipid microenvironment that governs ASIC1a expression and function at the membrane surface, especially peri-synaptic regions of dendritic spines, through an electrostatic interaction with anionic phospholipids.Competing Interest StatementThe authors have declared no competing interest.