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 Ca2+ 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. (C) 2010 Published by Elsevier Ltd on behalf of IBRO.