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

作者：Lingyong Li, Shaorui Chen, Menghua Zhou, Li Wang, De‐Pei Li, Hong Chen, Garam Lee, Vasanthi Jayaraman, Hui‐Lin Pan · 发表于：Cell Reports · 年份：2021 · DOI：10.1016/j.celrep.2021.109396 · 被引用次数：46 · 研究领域：Neuroscience and Neuropharmacology Research、Ion channel regulation and function、Pain Mechanisms and Treatments

Many neurological disorders show an increased prevalence of GluA2-lacking, Ca 2+ -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 2+ 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 2+ permeability of postsynaptic AMPARs.