NMDA receptor activity downregulates KCC2 resulting in depolarizing GABAA receptor-mediated currents

被引：228

作者：

Lee, Henry H. C. ^{[1
]}

Deeb, Tarek Z. ^{[1
]}

Walker, Joshua A. ^{[1
]}

Davies, Paul A. ^{[1
]}

Moss, Stephen J. ^{[1
,2
]}

机构：

[1] Tufts Univ, Dept Neurosci, Boston, MA 02111 USA

[2] UCL, Dept Neurosci Physiol & Pharmacol, London, England

来源：

NATURE NEUROSCIENCE | 2011年 / 14卷 / 06期

基金：

美国国家卫生研究院;

关键词：

TEMPORAL-LOBE EPILEPSY; K-CL COTRANSPORTER; CATION-CHLORIDE COTRANSPORTERS; NEURONAL-SPECIFIC ISOFORM; POSTNATAL RAT BRAINS; SPINAL-CORD-INJURY; HIPPOCAMPAL SLICE; NEUROPATHIC PAIN; GLUTAMATE; PHOSPHORYLATION;

D O I：

10.1038/nn.2806

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

KCC2 is a neuron-specific K+-Cl- co-transporter that maintains a low intracellular Cl-concentration that is essential for hyperpolarizing inhibition mediated by GABA(A) receptors. Deficits in KCC2 activity occur in disease states associated with pathophysiological glutamate release. However, the mechanisms by which elevated glutamate alters KCC2 function are unknown. The phosphorylation of KCC2 residue Ser940 is known to regulate its surface activity. We found that NMDA receptor activity and Ca2+ influx caused the dephosphorylation of Ser940 in dissociated rat neurons, leading to a loss of KCC2 function that lasted longer than 20 min. Protein phosphatase 1 mediated the dephosphorylation events of Ser940 that coincided with a deficit in hyperpolarizing GABAergic inhibition resulting from the loss of KCC2 activity. Blocking dephosphorylation of Ser940 reduced the glutamate-induced downregulation of KCC2 and substantially improved the maintenance of hyperpolarizing GABAergic inhibition. Reducing the downregulation of KCC2 therefore has therapeutic potential in the treatment of neurological disorders.

引用

页码：736 / U390

页数：9

共 51 条

[1] Tonic activation of group I mGluRs modulates inhibitory synaptic strength by regulating KCC2 activity [J].