Table_1_The α2δ-1-NMDA receptor complex and its potential as a therapeutic target for ischemic stroke.DOC

N-methyl-D-aspartate receptors (NMDARs) play a critical role in excitotoxicity caused by ischemic stroke, but NMDAR antagonists have failed to be translated into clinical practice for treating stroke patients. Recent studies suggest that targeting the specific protein–protein interactions that regulate NMDARs may be an effective strategy to reduce excitotoxicity associated with brain ischemia. α2δ-1 (encoded by the Cacna2d1 gene), previously known as a subunit of voltage-gated calcium channels, is a binding protein of gabapentinoids used clinically for treating chronic neuropathic pain and epilepsy. Recent studies indicate that α2δ-1 is an interacting protein of NMDARs and can promote synaptic trafficking and hyperactivity of NMDARs in neuropathic pain conditions. In this review, we highlight the newly identified roles of α2δ-1-mediated NMDAR activity in the gabapentinoid effects and NMDAR excitotoxicity during brain ischemia as well as targeting α2δ-1-bound NMDARs as a potential treatment for ischemic stroke.

N-甲基-D-天冬氨酸受体（N-methyl-D-aspartate receptors, NMDARs）在缺血性脑卒中引发的兴奋性毒性中发挥关键作用，但NMDAR拮抗剂尚未能转化为临床可用的脑卒中治疗方案。近期研究显示，靶向调控NMDARs的特异性蛋白质-蛋白质相互作用，或可成为减轻脑缺血相关兴奋性毒性的有效策略。α2δ-1（由Cacna2d1基因编码）此前被认定为电压门控钙通道（voltage-gated calcium channels）的一个亚基，同时也是临床用于治疗慢性神经性疼痛与癫痫的加巴喷丁类（gabapentinoids）药物的结合蛋白。最新研究表明，α2δ-1可与NMDARs发生相互作用，并在神经性疼痛状态下促进NMDARs的突触转运与过度激活。本综述重点阐述了α2δ-1介导的NMDAR活性在加巴喷丁类药物作用及脑缺血过程中NMDAR兴奋性毒性方面的新发现功能，并探讨了靶向结合α2δ-1的NMDARs作为缺血性脑卒中潜在治疗手段的可行性。