The α2δ-1-NMDA Receptor Complex Is Critically Involved in Neuropathic Pain Development and Gabapentin Therapeutic Actions.
The α2δ-1-NMDA Receptor Complex Is Critically Involved in Neuropathic Pain Development and Gabapentin Therapeutic Actions.
复制标题
DOI：
10.1016/j.celrep.2018.02.021
复制
发表时间：
2018-02-27
期刊：
影响因子：
8.8
通讯作者：
Pan HL
中科院分区：
文献类型：
--
作者：
Chen J;Li L;Chen SR;Chen H;Xie JD;Sirrieh RE;MacLean DM;Zhang Y;Zhou MH;Jayaraman V;Pan HL
α2δ-1，俗称电压激活钙通道亚基，是加巴喷丁类药物的结合部位，用于治疗神经病理性疼痛和癫痫。然而，目前尚不清楚α2δ-1如何参与神经病理性疼痛和加巴喷丁样活性。在这里，我们发现Cacna2d1的过度表达增强了脊髓背角神经元突触前和突触后的NMDAR活性，从而导致疼痛超敏。相反，Cacna2d1基因敲除或消融可使因神经损伤而增加的突触NMDAR活性正常化。α-2δ-1在啮齿动物和人脊髓中与NMDAR形成异构体复合体。α2δ-1与NMDAR的相互作用主要通过α2δ-1的C端进行，促进NMDAR的表面转运和突触靶向。加巴喷丁或α2δ-1 C末端干扰肽可使NMDAR突触靶向正常化，并使神经损伤后活性增加。因此，α2δ-1是一种与NMDAR相互作用的蛋白，可以增加NMDAR在神经病理性疼痛中的突触传递。加巴喷丁类化合物通过抑制α-2、δ-1-NMDAR复合体的前向运输来减轻神经病理性疼痛。Chen等人在神经病理性疼痛中，α-2δ-1通过其C端与α-2δ-1受体相互作用并促进其突触表达。加巴喷丁主要通过靶向α2δ-1结合的NMDA受体来减轻神经病理性疼痛。
α2δ-1, commonly known as a voltage-activated Ca2+ channel subunit, is a binding site of gabapentinoids used to treat neuropathic pain and epilepsy. However, it is unclear how α2δ-1 contributes to neuropathic pain and gabapentinoid actions. Here, we show that Cacna2d1 overexpression potentiates presynaptic and postsynaptic NMDAR activity of spinal dorsal horn neurons to cause pain hypersensitivity. Conversely, Cacna2d1 knockdown or ablation normalizes synaptic NMDAR activity increased by nerve injury. α2δ-1 forms a heteromeric complex with NMDARs in rodent and human spinal cords. The α2δ-1-NMDAR interaction predominantly occurs through the C terminus of α2δ-1 and promotes surface trafficking and synaptic targeting of NMDARs. Gabapentin or an α2δ-1 C terminus-interfering peptide normalizes NMDAR synaptic targeting and activity increased by nerve injury. Thus, α2δ-1 is an NMDAR-interacting protein that increases NMDAR synaptic delivery in neuropathic pain. Gabapentinoids reduce neuropathic pain by inhibiting forward trafficking of α2δ-1-NMDAR complexes. Chen et al. show that α2δ-1, through its C terminus, physically interacts with NMDA receptors and promotes synaptic expression of α2δ-1-NMDA receptor complexes in neuropathic pain. Gabapentin reduces neuropathic pain primarily by targeting α2δ-1-bound NMDA receptors.
登录
查看更多内容
影响因子：
4.8
作者：
Gee, NS;Brown, JP;Woodruff, GN
通讯作者：
Woodruff, GN
DOI：
10.1073/pnas.0504183102
发表时间：
2005-08-09
影响因子：
11.1
作者：
Cantí, C;Nieto-Rostro, M;Dolphin, AC
通讯作者：
Dolphin, AC
影响因子：
5.6
作者：
ANHUT, H;ASHMAN, P;BILL, PLA
通讯作者：
BILL, PLA
影响因子：
5.5
作者：
Chen, Shao-Rui;Hu, Yi-Min;Pan, Hui-Lin
通讯作者：
Pan, Hui-Lin
影响因子：
64.5
作者：
Eroglu C;Allen NJ;Susman MW;O'Rourke NA;Park CY;Ozkan E;Chakraborty C;Mulinyawe SB;Annis DS;Huberman AD;Green EM;Lawler J;Dolmetsch R;Garcia KC;Smith SJ;Luo ZD;Rosenthal A;Mosher DF;Barres BA
通讯作者：
Barres BA