title: N-methyl-D-aspartate receptor- and calpain-mediated proteolytic cleavage of K+-Cl- cotransporter-2 impairs spinal chloride homeostasis in neuropathic pain.
abstract: 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.
authors.affiliation: Center for Neuroscience and Pain Research, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Hong-Yi
authors.initials: HY
authors.lastname: Zhou
authors.forename: Shao-Rui
authors.initials: SR
authors.lastname: Chen
authors.forename: Hee-Sun
authors.initials: HS
authors.lastname: Byun
authors.forename: Hong
authors.initials: H
authors.lastname: Chen
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Hee-Dong
authors.initials: HD
authors.lastname: Han
authors.forename: Gabriel
authors.initials: G
authors.lastname: Lopez-Berestein
authors.forename: Anil K
authors.initials: AK
authors.lastname: Sood
authors.forename: Hui-Lin
authors.initials: HL
authors.lastname: Pan
mesh_terms: D000818:Animals; D001692:Biological Transport; D002154:Calpain / Q000378:metabolism*; D002712:Chlorides / Q000737:chemistry*; D004594:Electrophysiology / Q000379:methods; D018698:Glutamic Acid / Q000378:metabolism; D006706:Homeostasis; D008297:Male; D009437:Neuralgia / Q000378:metabolism*; D009473:Neuronal Plasticity; D010146:Pain; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry* / Q000378:metabolism; D027981:Symporters / Q000737:chemistry*; D013569:Synapses / Q000378:metabolism; D000096922:K Cl- Cotransporters
chemical_list: D002154:Calpain; D002712:Chlorides; D018698:Glutamic Acid; D034741:RNA, Small Interfering; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D027981:Symporters; D000096922:K Cl- Cotransporters