Huang Yuying, Chen Shao-Rui, Pan Hui-Lin
Department of Anesthesiology and Perioperative Medicine, Center for Neuroscience and Pain Research, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
J Neurochem. 2025 Apr;169(4):e70064. doi: 10.1111/jnc.70064.
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-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 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 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 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.
慢性神经性疼痛是一种使人衰弱的病症，带来了重大的治疗挑战。与伤害性疼痛不同，神经性疼痛主要由初级传入神经与脊髓背角兴奋性神经元之间突触处的谷氨酸N-甲基-D-天冬氨酸受体（NMDARs）和/或钙通透性α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（CP-AMPARs）驱动。由Cacna2d1编码的α2δ-1蛋白，在历史上被认为是电压激活钙通道的一个亚基，是加巴喷丁类药物（如加巴喷丁和普瑞巴林）的主要靶点，这些药物被广泛用于治疗神经性疼痛和癫痫。然而，加巴喷丁类药物对钙通道活性的影响极小。最近的研究表明，α2δ-1在神经性疼痛中增强向脊髓的伤害性输入方面起关键作用。这一作用是通过其内在无序的C末端区域与磷酸化的NMDARs以及GluA1/GluA2亚基的动态物理相互作用介导的。α2δ-1不仅促进NMDARs的突触转运，还破坏脊髓背角中GluA1/GluA2亚基的异聚体组装。α2δ-1的核心功能是提高突触前和突触后位点的细胞内钙浓度，增强伤害性传递。因此，α2δ-1作为一个双重调节因子，协调NMDARs和GluA1同聚体CP-AMPARs的突触表达，这一功能是加巴喷丁类药物治疗作用的基础。通过抑制α2δ-1，加巴喷丁类药物降低与突触α2δ-1结合的NMDARs和CP-AMPARs的过度活性，从而抑制神经性疼痛特有的过度兴奋性突触传递。α2δ-1在协调谷氨酸能突触可塑性方面的这些新发现的作用表明，加巴喷丁类药物可重新用于治疗其他涉及突触NMDARs和CP-AMPARs失调的神经系统疾病。
