Postsynaptic Targeting and Mobility of Membrane Surface-Localized hASIC1a

Neurosci Bull. 2021 Feb;37(2):145-165. doi: 10.1007/s12264-020-00581-9.

Xing-Lei Song ^# ¹ ², Di-Shi Liu ^# ¹ ², Min Qiang ³, Qian Li ¹ ² ⁴, Ming-Gang Liu ¹ ² ⁴, Wei-Guang Li ¹ ² ⁴, Xin Qi ¹ ², Nan-Jie Xu ² ⁴, Guang Yang ³, Michael Xi Zhu ⁵, Tian-Le Xu ⁶ ⁷ ⁸

Affiliations

1 Center for Brain Science of Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
2 Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
3 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China.
4 Shanghai Research Center for Brain Science and Brain-Inspired Intelligence, Shanghai, 201210, China.
5 Department of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, 77030, USA. michael.x.zhu@uth.tmc.edu.
6 Center for Brain Science of Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China. xu-happiness@shsmu.edu.cn.
7 Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. xu-happiness@shsmu.edu.cn.
8 Shanghai Research Center for Brain Science and Brain-Inspired Intelligence, Shanghai, 201210, China. xu-happiness@shsmu.edu.cn.
# Contributed equally.

PMID: 32996060 DOI: 10.1007/s12264-020-00581-9

Abstract

Acid-sensing ion channels (ASICs), the main H⁺ receptors in the central nervous system, sense extracellular pH fluctuations and mediate cation influx. ASIC1a, the major subunit responsible for acid-activated current, is widely expressed in brain neurons, where it plays pivotal roles in diverse functions including synaptic transmission and plasticity. However, the underlying molecular mechanisms for these functions remain mysterious. Using extracellular epitope tagging and a novel antibody recognizing the hASIC1a ectodomain, we examined the membrane targeting and dynamic trafficking of hASIC1a in cultured cortical neurons. Surface hASIC1a was distributed throughout somata and dendrites, clustered in spine heads, and co-localized with postsynaptic markers. By extracellular pHluorin tagging and fluorescence recovery after photobleaching, we detected movement of hASIC1a in synaptic spine heads. Single-particle tracking along with use of the anti-hASIC1a ectodomain antibody revealed long-distance migration and local movement of surface hASIC1a puncta on dendrites. Importantly, enhancing synaptic activity with brain-derived neurotrophic factor accelerated the trafficking and lateral mobility of hASIC1a. With this newly-developed toolbox, our data demonstrate the synaptic location and high dynamics of functionally-relevant hASIC1a on the surface of excitatory synapses, supporting its involvement in synaptic functions.

Keywords

ASIC1a; Brain-derived neurotrophic factor; Membrane trafficking; Surface labeling; Synaptic function; Visualization.

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