Downregulation of Kv4.2 channels mediated by NR2B-containing NMDA receptors in cultured hippocampal neurons.
Somatodendritic Kv4.2 channels mediate transient A-type potassium currents (I(A)), and play critical roles in controlling neuronal excitability and modulating synaptic plasticity. Our studies have shown an NMDA receptor-dependent downregulation of Kv4.2 and I(A). NMDA receptors are heteromeric complexes of NR1 combined with NR2A-NR2D, mainly NR2A and NR2B. Here, we investigate NR2B receptor-mediated modulation of Kv4.2 and I(A) in cultured hippocampal neurons. Application of glutamate caused a reduction in total Kv4.2 protein levels and Kv4.2 clusters, and produced a hyperpolarized shift in the inactivation curve of I(A). The effects of glutamate on Kv4.2 and I(A) were inhibited by pretreatment of NR2B-selective antagonists. NR2B-containing NMDA receptors are believed to be located predominantly extrasynaptically. Like application of glutamate, selective activation of extrasynaptic NMDA receptors caused a reduction in total Kv4.2 protein levels and Kv4.2 clusters, which was also blocked by NR2B-selective antagonists. In contrast, specific stimulation of synaptic NMDA receptors had no effect on Kv4.2. In addition, the influx of Ca(2+) was essential for extrasynaptic modulation of Kv4.2. Calpain inhibitors prevented the reduction of total Kv4.2 protein levels following activation of extrasynaptic NMDA receptors. These results demonstrate that the glutamate-induced downregulation of Kv4.2 and I(A) is mediated by NR2B-containing NMDA receptors and is linked to proteolysis by calpain, which might contribute to the development of neuronal hyperexcitability and neurodegenerative diseases.
Lei
Z
Z
Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Deng
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P
Li
Y
Y
Xu
Z C
ZC
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002154:Calpain / Q000378:metabolism; D002478:Cells, Cultured / Q000378:metabolism; D003712:Dendrites / Q000187:drug effects / Q000502:physiology; D015536:Down-Regulation; D018698:Glutamic Acid / Q000378:metabolism; D006023:Glycoproteins / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051672:Shal Potassium Channels / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects / Q000502:physiology
D006023:Glycoproteins; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D051672:Shal Potassium Channels; C039304:calpain inhibitors; D018698:Glutamic Acid; D002154:Calpain; D002118:Calcium