Rabphilin-3A undergoes phase separation to regulate GluN2A mobility and surface clustering

Lei Yang, Mengping Wei, Yangzhen Wang, Jingtao Zhang, Sen Liu, Mengna Liu, Shanshan Wang, Ke Li, Zhaoqi Dong and Chen Zhang ()
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Lei Yang: Capital Medical University
Mengping Wei: Capital Medical University
Yangzhen Wang: Tsinghua University
Jingtao Zhang: Capital Medical University
Sen Liu: Capital Medical University
Mengna Liu: Peking University
Shanshan Wang: Peking University
Ke Li: Capital Medical University
Zhaoqi Dong: Capital Medical University
Chen Zhang: Capital Medical University

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract N-methyl-D-aspartate receptors (NMDARs) are essential for excitatory neurotransmission and synaptic plasticity. GluN2A and GluN2B, two predominant Glu2N subunits of NMDARs in the hippocampus and the cortex, display distinct clustered distribution patterns and mobility at synaptic and extrasynaptic sites. However, how GluN2A clusters are specifically organized and stabilized remains poorly understood. Here, we found that the previously reported GluN2A-specific binding partner Rabphilin-3A (Rph3A) has the ability to undergo phase separation, which relies on arginine residues in its N-terminal domain. Rph3A phase separation promotes GluN2A clustering by binding GluN2A’s C-terminal domain. A complex formed by Rph3A, GluN2A, and the scaffolding protein PSD95 promoted Rph3A phase separation. Disrupting Rph3A’s phase separation suppressed the synaptic and extrasynaptic surface clustering, synaptic localization, stability, and synaptic response of GluN2A in hippocampal neurons. Together, our results reveal the critical role of Rph3A phase separation in determining the organization and stability of GluN2A in the neuronal surface.

Date: 2023
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DOI: 10.1038/s41467-023-36046-6

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