The DOI matches its Crossref record; 4 of the 4 references it cites were found in a registry or an index.
N-Methyl-d-aspartate Receptor- and Calpain-mediated Proteolytic Cleavage of K+-Cl− Cotransporter-2 Impairs Spinal Chloride Homeostasis in Neuropathic Pain
Open accessAbstract
Loss of synaptic inhibition by γ-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 μ-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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Cites
Neuronal plasticity: Increasing the gain in pain
Woolf, C. J., & Salter, M. W. (2000) · Science · doi:10.1126/science.288.5472.1765 · Cited by 3,781 · cited 1×
“Activity-dependent synaptic plasticity at the spinal cord level is fundamentally important to the development of neuropathic pain (1).”
BackgroundHo Kim, S., & Mo Chung, J. (1992) · Pain · doi:10.1016/0304-3959(92)90041-9 · Cited by 3,069
BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain
Coull, J. A. M., Beggs, S., Boudreau, D., Boivin, D., Tsuda, M., Inoue, K., Gravel, C., Salter, M. W., & De Koninck, Y. (2005) · Nature · doi:10.1038/nature04223 · Cited by 1,965
Shulga, A., Thomas-Crusells, J., Sigl, T., Blaesse, A., Mestres, P., Meyer, M., Yan, Q., Kaila, K., Saarma, M., Rivera, C., et al. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.5268-07.2008 · Cited by 137
Cited by
Chen, J., Li, L., Chen, S.-R., Chen, H., Xie, J.-D., Sirrieh, R. E., MacLean, D. M., Zhang, Y., Zhou, M.-H., Jayaraman, V., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.02.021 · Cited by 283
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Metadata
- Authors
- Zhou, H.-Y., Chen, S.-R., Byun, H.-S., Chen, H., Li, L., Han, H.-D., Lopez-Berestein, G., Sood, A. K., & Pan, H.-L.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2012-09
- Volume
- 287
- Issue
- 40
- Pages
- 33853-33864
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1969672804
- Cited by
- 159
- References
- 4
- FWCI
- 6.42
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- Zhou, H.-Y., Chen, S.-R., Byun, H.-S., Chen, H., Li, L., Han, H.-D., Lopez-Berestein, G., Sood, A. K., & Pan, H.-L. (2012). N-Methyl-d-aspartate Receptor- and Calpain-mediated Proteolytic Cleavage of K+-Cl− Cotransporter-2 Impairs Spinal Chloride Homeostasis in Neuropathic Pain. Journal of Biological Chemistry. https://doi.org/10.1074/jbc.m112.395830
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