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Glutamate transporters regulate extrasynaptic NMDA receptor modulation of Kv2.1 potassium channels.

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 (I(K)). 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 I(K). 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.

Pubmed ID: 18753382 RIS Download

Mesh terms: Amino Acid Transport System X-AG | Analysis of Variance | Animals | Animals, Newborn | Cells, Cultured | Cerebral Cortex | Dizocilpine Maleate | Excitatory Amino Acid Agonists | Excitatory Amino Acid Antagonists | Hippocampus | Intracellular Signaling Peptides and Proteins | Male | Membrane Potentials | Membrane Proteins | N-Methylaspartate | Neurons | Organ Culture Techniques | Patch-Clamp Techniques | Pentylenetetrazole | Rats | Rats, Sprague-Dawley | Receptors, N-Methyl-D-Aspartate | Seizures | Shab Potassium Channels | Synapses

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Associated grants

  • Agency: NIAAA NIH HHS, Id: R01 AA009986-14
  • Agency: NIAAA NIH HHS, Id: AA010983
  • Agency: NIAAA NIH HHS, Id: R01 AA010983-11
  • Agency: NIAAA NIH HHS, Id: R29 AA010983
  • Agency: NIAAA NIH HHS, Id: F32 AA016450
  • Agency: NIAAA NIH HHS, Id: R37 AA009986
  • Agency: NIAAA NIH HHS, Id: AA016450
  • Agency: NIAAA NIH HHS, Id: AA09986
  • Agency: NIAAA NIH HHS, Id: F32 AA016450-02
  • Agency: NIAAA NIH HHS, Id: R01 AA010983
  • Agency: NIAAA NIH HHS, Id: R01 AA009986

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