TY - JOUR
T1 - Zinc alleviates pain through high-affinity binding to the NMDA receptor NR2A subunit
AU - Nozaki, Chihiro
AU - Vergnano, Angela Maria
AU - Filliol, Dominique
AU - Ouagazzal, Abdel Mouttalib
AU - Le Goff, Anne
AU - Carvalho, Stéphanie
AU - Reiss, David
AU - Gaveriaux-Ruff, Claire
AU - Neyton, Jacques
AU - Paoletti, Pierre
AU - Kieffer, Brigitte L.
N1 - Funding Information:
E. Schwartz for comments on the manuscript. We also thank Victor Faundez (Emory University) for the gift of the ZnT3 antibody. This research was supported by the Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), the Université de Strasbourg, the Agence Nationale de la Recherche (France) grant SynapticZinc (P.P. and B.K.), the US National Institutes of Health, National Institue on Drug Abuse grant DA05010 (B.K.) and an Equipe Fondation pour la Recherche Médicale (FRM) grant (P.P.). C.N. was supported by the FRM and A.M.V. by the Région Ile-de-France.
PY - 2011/8
Y1 - 2011/8
N2 - Zinc is abundant in the central nervous system and regulates pain, but the underlying mechanisms are unknown. In vitro studies have shown that extracellular zinc modulates a plethora of signaling membrane proteins, including NMDA receptors containing the NR2A subunit, which display exquisite zinc sensitivity. We created NR2A-H128S knock-in mice to investigate whether Zn2+-NR2A interaction influences pain control. In these mice, high-affinity (nanomolar) zinc inhibition of NMDA currents was lost in the hippocampus and spinal cord. Knock-in mice showed hypersensitivity to radiant heat and capsaicin, and developed enhanced allodynia in inflammatory and neuropathic pain models. Furthermore, zinc-induced analgesia was completely abolished under both acute and chronic pain conditions. Our data establish that zinc is an endogenous modulator of excitatory neurotransmission in vivo and identify a new mechanism in pain processing that relies on NR2A NMDA receptors. The study also potentially provides a molecular basis for the pain-relieving effects of dietary zinc supplementation.
AB - Zinc is abundant in the central nervous system and regulates pain, but the underlying mechanisms are unknown. In vitro studies have shown that extracellular zinc modulates a plethora of signaling membrane proteins, including NMDA receptors containing the NR2A subunit, which display exquisite zinc sensitivity. We created NR2A-H128S knock-in mice to investigate whether Zn2+-NR2A interaction influences pain control. In these mice, high-affinity (nanomolar) zinc inhibition of NMDA currents was lost in the hippocampus and spinal cord. Knock-in mice showed hypersensitivity to radiant heat and capsaicin, and developed enhanced allodynia in inflammatory and neuropathic pain models. Furthermore, zinc-induced analgesia was completely abolished under both acute and chronic pain conditions. Our data establish that zinc is an endogenous modulator of excitatory neurotransmission in vivo and identify a new mechanism in pain processing that relies on NR2A NMDA receptors. The study also potentially provides a molecular basis for the pain-relieving effects of dietary zinc supplementation.
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U2 - 10.1038/nn.2844
DO - 10.1038/nn.2844
M3 - Article
C2 - 21725314
AN - SCOPUS:79960837047
SN - 1097-6256
VL - 14
SP - 1017
EP - 1022
JO - Nature Neuroscience
JF - Nature Neuroscience
IS - 8
ER -