α2δ‐1‐Linked NMDA and AMPA Receptors in Neuropathic Pain and Gabapentinoid Action

作者：Yuying Huang, Shaorui Chen, Hui‐Lin Pan · 发表于：Journal of Neurochemistry · 年份：2025 · DOI：10.1111/jnc.70064 · 被引用次数：21 · 研究领域：Pain Mechanisms and Treatments、Neuroscience and Neuropharmacology Research、Ion channel regulation and function

ABSTRACT Chronic neuropathic pain is a debilitating condition that presents a significant therapeutic challenge. Unlike nociceptive pain, neuropathic pain is predominantly driven by glutamate NMDA receptors (NMDARs) and/or Ca 2+ ‐permeable AMPA receptors (CP‐AMPARs) at synapses between primary afferent nerves and excitatory neurons in the spinal dorsal horn. The α2δ‐1 protein, encoded by Cacna2d1 and historically recognized as a subunit of voltage‐activated Ca 2+ channels, is the primary target of gabapentinoids, such as gabapentin and pregabalin, which are widely prescribed for neuropathic pain and epilepsy. However, gabapentinoids have minimal effects on Ca 2+ channel activity. Recent studies reveal that α2δ‐1 plays a pivotal role in amplifying nociceptive input to the spinal cord in neuropathic pain. This action is mediated through its dynamic physical interactions with phosphorylated NMDARs and GluA1/GluA2 subunits via its intrinsically disordered C‐terminal region. α2δ‐1 not only promotes synaptic trafficking of NMDARs but also disrupts heteromeric assembly of GluA1/GluA2 subunits in the spinal dorsal horn. The central function of α2δ‐1 is to elevate intracellular Ca 2+ concentrations at both presynaptic and postsynaptic sites, augmenting nociceptive transmission. Consequently, α2δ‐1 serves as a dual regulator coordinating synaptic expression of NMDARs and GluA1 homomeric CP‐AMPARs, a function that underlies the therapeutic actions of gabapentinoids. By inhibiting α2δ‐1,...