α2δ‐1‐Linked <scp>NMDA</scp> and <scp>AMPA</scp> Receptors in Neuropathic Pain and Gabapentinoid Action
Yuying Huang, Shaorui Chen, Hui‐Lin Pan
Abstract
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, gabapentinoids reduce the hyperactivity of synaptic α2δ‐1‐bound NMDARs and CP‐AMPARs, thereby dampening the excessive excitatory synaptic transmission characteristic of neuropathic pain. These newly identified roles of α2δ‐1 in orchestrating glutamatergic synaptic plasticity suggest that gabapentinoids could be repurposed for treating other neurological disorders involving dysregulated synaptic NMDARs and CP‐AMPARs. image