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Dynamic regulation of the Kv2.1 voltage-gated potassium channel during brain ischemia through neuroglial interaction.

The physiological significance of neuroglial interactions in the CNS has been emphasized in neurological conditions such as epilepsy and brain ischemia. The Kv2.1 voltage-gated potassium channel is unique in its ability to form large clusters in the plasma membrane of neuronal cell bodies. We have previously shown that brain ischemia causes rapid dephosphorylation of Kv2.1 subunits and resultant activation of the ion channel function. However, the physiological significance of the channel clustering is unknown. Here we present evidence that clustered Kv2.1 channels in the neuronal plasma membrane are juxtaposed to axosomatic synapses and associated with astrocytic processes expressing high levels of glutamate transporters. In acute cortical slices, ischemic stress rapidly resulted in the dephosphorylation and dispersion of Kv2.1. Selective inhibition of metabolism in astrocytes was sufficient to induce Kv2.1 dephosphorylation in neurons. Interestingly, these effects were blocked by the antagonists of ionotropic glutamate receptors, indicating the involvement of glutamate as the signal mediator between astrocytes and neurons. Furthermore, the pharmacological inhibition of glial glutamate transporter GLT-1 induced the similar Kv2.1 dephosphorylation, whereas exogenous glutamate alone was not efficacious. These results suggest that ischemic stress rapidly causes the dysfunction of glutamate transporters in astrocytes and resultant accumulation of glutamate in the extracellular space. The elevated glutamate may subsequently activate ionotropic glutamate receptors and result in the dephosphorylation of Kv2.1 in neurons. These findings implicate that Kv2.1 clusters are strategically situated at neuroglial junctions to achieve the rapid modulation after ischemic stress via glutamate signaling.

Pubmed ID: 18716211 RIS Download

Mesh terms: Acute Disease | Animals | Astrocytes | Brain Ischemia | Cell Membrane | Cerebral Cortex | Excitatory Amino Acid Transporter 2 | Glutamic Acid | In Vitro Techniques | Intercellular Junctions | Male | Neuroglia | Phosphorylation | Pyramidal Cells | Rats | Rats, Sprague-Dawley | Shab Potassium Channels | Tissue Distribution

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Associated grants

  • Agency: NINDS NIH HHS, Id: R01 NS040338-05A2
  • Agency: NINDS NIH HHS, Id: NS40338
  • Agency: NIMH NIH HHS, Id: R01 MH065488-05
  • Agency: NIMH NIH HHS, Id: R01 MH065488
  • Agency: NIMH NIH HHS, Id: MH65488
  • Agency: NINDS NIH HHS, Id: R01 NS040338

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