| First Author | Li L | Year | 2021 |
| Journal | Cell Rep | Volume | 36 |
| Issue | 3 | Pages | 109396 |
| PubMed ID | 34289359 | Mgi Jnum | J:334264 |
| Mgi Id | MGI:6879404 | Doi | 10.1016/j.celrep.2021.109396 |
| Citation | Li L, et al. (2021) alpha2delta-1 switches the phenotype of synaptic AMPA receptors by physically disrupting heteromeric subunit assembly. Cell Rep 36(3):109396 |
| abstractText | 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 alpha2delta-1. Overexpressing alpha2delta-1, previously regarded as a Ca(2+) channel subunit, augments CP-AMPAR levels at the cell surface and synapse. Mechanistically, alpha2delta-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, alpha2delta-1 diminishes the availability and synaptic expression of GluA1/GluA2 heterotetramers in the spinal cord in neuropathic pain. Inhibiting alpha2delta-1 with gabapentin or disrupting the alpha2delta-1-AMPAR complex fully restores the intracellular assembly and synaptic dominance of heteromeric GluA1/GluA2 receptors. Thus, alpha2delta-1 is a pivotal AMPAR-interacting protein that controls the subunit composition and Ca(2+) permeability of postsynaptic AMPARs. |
