Spinal α2δ-1 induces GluA3 degradation to regulate assembly of calcium-permeable AMPA receptors and pain hypersensitivity.

ABSTRACT: The increased prevalence of GluA2-lacking, Ca2+-permeable AMPA receptors (CP-AMPARs) at spinal cord sensory synapses amplifies nociceptive transmission and maintains chronic neuropathic pain. Nerve injury-induced upregulation of α2δ-1 disrupts the assembly of GluA1/GluA2 heteromers, favoring the synaptic incorporation of GluA1 homotetramers in the spinal dorsal horn. Although GluA1-GluA3 subunits are broadly expressed, whether α2δ-1 regulates GluA3-containing AMPARs remains unknown. Here, we unexpectedly found that coexpression with α2δ-1-but not α2δ-2 or α2δ-3-diminished GluA3 AMPAR currents and protein levels, an effect blocked by pregabalin, an α2δ-1 C-terminus peptide, or proteasome inhibition. Both nerve injury and α2δ-1 overexpression reduced protein levels of GluA3 and GluA2/GluA3 h

SUBMITTER: Zhou MH 

PROVIDER: S-EPMC12721899 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature