{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T06:57:28Z","timestamp":1788245848958,"version":"build-2803163510"},"reference-count":76,"publisher":"American Society for Clinical Investigation","issue":"1","license":[{"start":{"date-parts":[[2026,1,2]],"date-time":"2026-01-02T00:00:00Z","timestamp":1767312000000},"content-version":"vor","delay-in-days":71,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["NS,101880"],"award-info":[{"award-number":["NS,101880"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,1,2]]},"abstract":"<jats:p>\n                    The increased prevalence of GluA2-lacking, Ca\n                    <jats:sup>2+<\/jats:sup>\n                    -permeable AMPA receptors (CP-AMPARs) at spinal cord sensory synapses amplifies nociceptive transmission and maintains chronic neuropathic pain. Nerve injury\u2013induced upregulation of \u03b12\u03b4-1 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 \u03b12\u03b4-1 regulates GluA3-containing AMPARs remains unknown. Here, we unexpectedly found that coexpression with \u03b12\u03b4-1 \u2014 but not \u03b12\u03b4-2 or \u03b12\u03b4-3 \u2014 diminished GluA3 AMPAR currents and protein levels, an effect blocked by pregabalin, an \u03b12\u03b4-1 C-terminus peptide, or proteasome inhibition. Both nerve injury and \u03b12\u03b4-1 overexpression reduced protein levels of GluA3 and GluA2\/GluA3 heteromers in the spinal cord. Furthermore, \u03b12\u03b4-1 coexpression or nerve injury increased GluA3 ubiquitination, with K861 at the C-terminus of GluA3 identified as a key ubiquitination site mediating \u03b12\u03b4-1\u2013induced GluA3 degradation. Additionally, intrathecal delivery of the\n                    <jats:italic>Gria3<\/jats:italic>\n                    gene reversed nerve injury\u2013induced nociceptive hypersensitivity and synaptic CP-AMPARs by restoring protein levels of GluA3 and GluA2\/GluA3 heteromers in the spinal cord. These findings reveal that \u03b12\u03b4-1 promotes GluA1 homotetramer assembly and synaptic CP-AMPAR expression by driving ubiquitin-proteasome\u2013mediated degradation of GluA3, providing insights into the molecular mechanisms of neuropathic pain and the therapeutic actions of gabapentinoids.\n                  <\/jats:p>","DOI":"10.1172\/jci193349","type":"journal-article","created":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T16:00:48Z","timestamp":1761235248000},"source":"Crossref","is-referenced-by-count":5,"title":["Spinal \u03b12\u03b4-1 induces GluA3 degradation to regulate assembly of calcium-permeable AMPA receptors and pain 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