Li Lingyong, Chen Shao-Rui, Zhou Meng-Hua, Wang Li, Li De-Pei, Chen Hong, Lee Garam, Jayaraman Vasanthi, Pan Hui-Lin
Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Cell Rep. 2021 Jul 20;36(3):109396. doi: 10.1016/j.celrep.2021.109396.
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.
许多神经疾病中，缺乏GluA2的、钙离子通透的α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（CP-AMPARs）的患病率增加，这会显著改变突触功能。然而，这种独特的突触可塑性背后的分子机制仍然是个谜。在这里，我们表明神经损伤通过α2δ-1增强脊髓背角突触后而非突触前的CP-AMPARs。过表达α2δ-1（以前被认为是一种钙通道亚基）会增加细胞表面和突触处的CP-AMPAR水平。从机制上讲，α2δ-1通过其C末端与GluA1和GluA2发生物理相互作用，抑制GluA1/GluA2异源组装，并增加GluA2在内质网中的保留。因此，α2δ-1减少了神经性疼痛时脊髓中GluA1/GluA2异源四聚体的可用性和突触表达。用加巴喷丁抑制α2δ-1或破坏α2δ-1-AMPAR复合物可完全恢复异源GluA1/GluA2受体的细胞内组装和突触优势。因此，α2δ-1是一种关键的与AMPAR相互作用的蛋白，可控制突触后AMPAR的亚基组成和钙离子通透性。
