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Papers of the Week

Papers: 17 Jul 2021 - 23 Jul 2021

Animal Studies, Pharmacology/Drug Development

2021 Jul 20

Cell Rep



Editor's Pick

α2δ-1 switches the phenotype of synaptic AMPA receptors by physically disrupting heteromeric subunit assembly.


Li L, Chen S-R, Zhou M-H, Wang L, Li D-P, Chen H, Lee G, Jayaraman V, Pan H-L
Cell Rep. 2021 Jul 20; 36(3):109396.
PMID: 34289359.


Many neurological disorders show an increased prevalence of GluA2-lacking, Ca-permeable AMPA receptors (CP-AMPARs), which dramatically alters synaptic function. However, the molecular mechanism underlying this distinct synaptic plasticity remains enigmatic. Here, we show that nerve injury potentiates postsynaptic, but not presynaptic, CP-AMPARs in the spinal dorsal horn via α2δ-1. Overexpressing α2δ-1, previously regarded as a Ca channel subunit, augments CP-AMPAR levels at the cell surface and synapse. Mechanistically, α2δ-1 physically interacts with both GluA1 and GluA2 via its C terminus, inhibits the GluA1/GluA2 heteromeric assembly, and increases GluA2 retention in the endoplasmic reticulum. Consequently, α2δ-1 diminishes the availability and synaptic expression of GluA1/GluA2 heterotetramers in the spinal cord in neuropathic pain. Inhibiting α2δ-1 with gabapentin or disrupting the α2δ-1-AMPAR complex fully restores the intracellular assembly and synaptic dominance of heteromeric GluA1/GluA2 receptors. Thus, α2δ-1 is a pivotal AMPAR-interacting protein that controls the subunit composition and Ca permeability of postsynaptic AMPARs.