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Inhibition of glutamate transporters couples to Kv4.2 dephosphorylation through activation of extrasynaptic NMDA receptors.

Neuroscience | Jan 13, 2010

Activation of glutamate receptors is known to modulate K(+) channel surface trafficking, phosphorylation, and function, and increasing evidence has implicated K(+) channels in plastic changes in glutamatergic synapses. Kv4.2 channels control the amplitude of back-propagating action potentials and shape postsynaptic responses in hippocampus, and synaptic glutamate receptor activation leads to increased phosphorylation of Kv4.2 channels that is associated with enhanced synaptic plasticity. Thus, we investigated the possibility that activation of extrasynaptic NMDA-type glutamate receptors couples to Kv4.2 channel dephosphorylation. In hippocampal neurons, we found that selective activation of extrasynaptic NMDA receptors dephosphorylates Kv4.2 channels, and driving synaptic activity increases phosphorylation of Kv4.2. We also observed that Ca(2+) entry through NMDA receptors is necessary for dephosphorylation of Kv4.2 channels. Consistent with a synaptic and extrasynaptic localization at hippocampal synapses, a fraction of Kv4.2 channel clusters was found to localize outside of pre- and postsynaptic markers. Excitatory amino acid transporters (EAATs) regulate ambient extracellular glutamate levels that active extrasynaptic NMDA receptors, and inhibition of glutamate uptake by blocking EAATs with the non-selective transporter inhibitor dl-threo-beta-benzyloxyaspartic acid (TBOA) or the EAAT1/3 selective inhibitor l-serine O-sulfate (SOS) dephosphorylates Kv4.2 channels. These findings in conjunction with previous reports support the interesting possibility that synaptic and extrasynaptic NMDA receptors bi-directionally regulate phosphorylation levels of Kv4.2 channels in hippocampus. Moreover, we observed that EAAT activity controls extrasynaptic NMDA receptor modulation of Kv4.2 channel dephosphorylation.

Pubmed ID: 19850106 RIS Download

Mesh terms: Amino Acid Transport System X-AG | Animals | Animals, Newborn | Calcium | Cluster Analysis | Hippocampus | In Vitro Techniques | Male | Mice | Mice, Inbred C3H | Pentylenetetrazole | Phosphorylation | Protein Transport | Rats | Rats, Sprague-Dawley | Receptors, N-Methyl-D-Aspartate | Seizures | Shal Potassium Channels

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Associated grants

  • Agency: NIAAA NIH HHS, Id: R01 AA010983-12A1
  • Agency: NIAAA NIH HHS, Id: AA010983
  • Agency: NIAAA NIH HHS, Id: K99 AA017922
  • Agency: NIAAA NIH HHS, Id: R29 AA010983
  • Agency: NIAAA NIH HHS, Id: K99 AA017922-01A1
  • Agency: NIAAA NIH HHS, Id: AA017922
  • Agency: NIAAA NIH HHS, Id: R01 AA010983
  • Agency: NIAAA NIH HHS, Id: R00 AA017922

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