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The Journal of Neuroscience, August 27, 2008, 28(35):8801-8809; doi:10.1523/JNEUROSCI.2405-08.2008

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Cellular/Molecular
Glutamate Transporters Regulate Extrasynaptic NMDA Receptor Modulation of Kv2.1 Potassium Channels

Patrick J. Mulholland, Ezekiel P. Carpenter-Hyland, Matthew C. Hearing, Howard C. Becker, John J. Woodward, and L. Judson Chandler

Department of Neurosciences and Center for Drug and Alcohol Programs, Medical University of South Carolina, Charleston, South Carolina 29425

Correspondence should be addressed to L. Judson Chandler, Department of Neurosciences and Center for Drug and Alcohol Programs, 67 President Street, Medical University of South Carolina, Charleston, SC. Email: chandj{at}musc.edu

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.

Key words: Kv2.1 channels; NMDA receptors; extrasynaptic; astroglia; glutamate transporters; extracellular

Received May 20, 2008; revised June 23, 2008; accepted July 23, 2008.

Correspondence should be addressed to L. Judson Chandler, Department of Neurosciences and Center for Drug and Alcohol Programs, 67 President Street, Medical University of South Carolina, Charleston, SC. Email: chandj{at}musc.edu






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