PT  - JOURNAL ARTICLE
AU  - Patrick J. Mulholland
AU  - Ezekiel P. Carpenter-Hyland
AU  - Matthew C. Hearing
AU  - Howard C. Becker
AU  - John J. Woodward
AU  - L. Judson Chandler
TI  - Glutamate Transporters Regulate Extrasynaptic NMDA Receptor Modulation of Kv2.1 Potassium Channels
AID  - 10.1523/JNEUROSCI.2405-08.2008
DP  - 2008 Aug 27
TA  - The Journal of Neuroscience
PG  - 8801--8809
VI  - 28
IP  - 35
4099  - http://www.jneurosci.org/content/28/35/8801.short
4100  - http://www.jneurosci.org/content/28/35/8801.full
SO  - J. Neurosci.2008 Aug 27; 28
AB  - Delayed-rectifier Kv2.1 potassium channels regulate somatodendritic excitability during periods of repetitive, high-frequency activity. Recent evidence suggests that Kv2.1 channel modulation is linked to glutamatergic neurotransmission. Because NMDA-type glutamate receptors are critical regulators of synaptic plasticity, we investigated NMDA receptor modulation of Kv2.1 channels in rodent hippocampus and cortex. Bath application of NMDA potently unclustered and dephosphorylated Kv2.1 and produced a hyperpolarizing shift in voltage-dependent activation of voltage-sensitive potassium currents (IK). In contrast, driving synaptic activity in Mg2+-free media to hyperactivate synaptic NMDA receptors had no effect on Kv2.1 channels, and moderate pentylenetetrazole-induced seizure activity in adult mice did not dephosphorylate hippocampal Kv2.1 channels. Selective activation of extrasynaptic NMDA receptors unclustered and dephosphorylated Kv2.1 channels and produced a hyperpolarizing shift in neuronal IK. In addition, inhibition of glutamate uptake rapidly activated NMDA receptors and dephosphorylated Kv2.1 channels. These observations demonstrate that regulation of intrinsic neuronal activity by Kv2.1 is coupled to extrasynaptic but not synaptic NMDA receptors. These data support a novel mechanism for glutamate transporters in regulation of neuronal excitability and plasticity through extrasynaptic NMDA receptor modulation of Kv2.1 channels.