Details

Autor(en) / Beteiligte

• Chen, Jinjun
• Li, Lingyong
• Chen, Shao-Rui
• Chen, Hong
• Xie, Jing-Dun
• Sirrieh, Rita E.
• MacLean, David M.
• Zhang, Yuhao
• Zhou, Meng-Hua
• Jayaraman, Vasanthi
• Pan, Hui-Lin

Titel

The α2δ-1-NMDA Receptor Complex Is Critically Involved in Neuropathic Pain Development and Gabapentin Therapeutic Actions

Ist Teil von

• Cell reports (Cambridge), 2018-02, Vol.22 (9), p.2307-2321

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2018

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. [Display omitted] •α2δ-1 forms a heteromeric complex with NMDARs, mainly through its C terminus domain•α2δ-1 is essential for nerve injury-induced pre- and postsynaptic NMDAR hyperactivity•α2δ-1 promotes synaptic and surface expression of α2δ-1-NMDAR complexes•α2δ-1-bound NMDARs are critical for neuropathic pain development and gabapentin actions 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.