Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 287, Issue 40, Pages 33853-33864Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M112.395830
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Funding
- National Institutes of Health [GM064830, NS045602, NS073935, GM092599, CA151668]
- N. G. and Helen T. Hawkins endowment
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Loss of synaptic inhibition by gamma-aminobutyric acid and glycine due to potassium chloride cotransporter-2 (KCC2) down-regulation in the spinal cord is a critical mechanism of synaptic plasticity in neuropathic pain. Here we present novel evidence that peripheral nerve injury diminishes glycine-mediated inhibition and induces a depolarizing shift in the reversal potential of glycine-mediated currents (E-glycine) in spinal dorsal horn neurons. Blocking glutamate N-methyl-D-aspartate (NMDA) receptors normalizes synaptic inhibition, E-glycine, and KCC2 by nerve injury. Strikingly, nerve injury increases calcium-dependent calpain activity in the spinal cord that in turn causes KCC2 cleavage at the C terminus. Inhibiting calpain blocks KCC2 cleavage induced by nerve injury and NMDA, thereby normalizing E-glycine. Furthermore, calpain inhibition or silencing of mu-calpain at the spinal level reduces neuropathic pain. Thus, nerve injury promotes proteolytic cleavage of KCC2 through NMDA receptor-calpain activation, resulting in disruption of chloride homeostasis and diminished synaptic inhibition in the spinal cord. Targeting calpain may represent a new strategy for restoring KCC2 levels and tonic synaptic inhibition and for treating chronic neuropathic pain.
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