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The α2δ-1-NMDA Receptor Complex Is Critically Involved in Neuropathic Pain Development and Gabapentin Therapeutic Actions.
- Source :
-
Cell reports [Cell Rep] 2018 Feb 27; Vol. 22 (9), pp. 2307-2321. - Publication Year :
- 2018
-
Abstract
- α2δ-1, commonly known as a voltage-activated Ca <superscript>2+</superscript> 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.<br /> (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Calcium Channels deficiency
Calcium Channels metabolism
Calcium Channels, L-Type chemistry
Gabapentin pharmacology
HEK293 Cells
Humans
Male
Mice, Knockout
Posterior Horn Cells metabolism
Posterior Horn Cells pathology
Protein Binding
Rats
Synapses metabolism
Calcium Channels, L-Type metabolism
Gabapentin therapeutic use
Neuralgia drug therapy
Neuralgia metabolism
Receptors, N-Methyl-D-Aspartate metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2211-1247
- Volume :
- 22
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Cell reports
- Publication Type :
- Academic Journal
- Accession number :
- 29490268
- Full Text :
- https://doi.org/10.1016/j.celrep.2018.02.021