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Ethanol disrupts NMDA receptor and astroglial EAAT2 modulation of Kv2.1 potassium channels in hippocampus.

Delayed-rectifier Kv2.1 channels are the principal component of voltage-sensitive K+ currents (I(K)) in hippocampal neurons and are critical regulators of somatodendritic excitability. In a recent study, we demonstrated that surface trafficking and phosphorylation of Kv2.1 channels is modulated by NMDA-type glutamate receptors and that astroglial excitatory amino acid transporters 2 (EAAT2) regulate the coupling of NMDA receptors and Kv2.1 channels. Because ethanol is known to acutely inhibit NMDA receptors, we sought to determine if NMDA receptor and astroglial EAAT2 modulation of Kv2.1 channels is impaired by ethanol in the rodent hippocampus. As expected, bath application of NMDA to hippocampal cultures reduced the size of Kv2.1 clusters and produced a hyperpolarizing shift in the voltage-dependent activation of I(K) that was associated with dephosphorylated Kv2.1 channels. Ethanol, applied acutely, prevented the hyperpolarizing shift in activation of I(K) induced by NMDA and restored Kv2.1 clustering and phosphorylation to near control levels. Ethanol also attenuated the dephosphorylation of Kv2.1 channels produced by the EAAT2 selective inhibitor dihydrokainic acid. These data demonstrate that acute ethanol disrupts changes in Kv2.1 channels that follow NMDA receptor activation and impairs astroglial regulation of the functional coupling between NMDA receptors and Kv2.1 channels.

Pubmed ID: 19185209 RIS Download

Mesh terms: Animals | Astrocytes | Cells, Cultured | Central Nervous System Depressants | Electrophysiology | Ethanol | Excitatory Amino Acid Antagonists | Excitatory Amino Acid Transporter 2 | Hippocampus | Kainic Acid | Patch-Clamp Techniques | Phosphorylation | Rats | Rats, Sprague-Dawley | Receptors, N-Methyl-D-Aspartate | Shab Potassium Channels

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Associated grants

  • Agency: NIAAA NIH HHS, Id: AA009986
  • 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: NCRR NIH HHS, Id: S10 RR015776
  • Agency: NIAAA NIH HHS, Id: R37 AA009986
  • Agency: NIAAA NIH HHS, Id: AA016450
  • Agency: NIAAA NIH HHS, Id: R01 AA010983-10
  • Agency: NIAAA NIH HHS, Id: R01 AA010983
  • Agency: NIAAA NIH HHS, Id: R01 AA009986
  • Agency: NCRR NIH HHS, Id: S10 RR015776-01A1

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NeuroMab

A national mouse monoclonal antibody generating resource for biochemical and immunohistochemical applications in mammalian brain. NeuroMabs are generated from mice immunized with synthetic and recombinant immunogens corresponding to components of the neuronal proteome as predicted from genomic and other large-scale cloning efforts. Comprehensive biochemical and immunohistochemical analyses of human, primate and non-primate mammalian brain are incorporated into the initial NeuroMab screening procedure. This yields a subset of mouse mAbs that are optimized for use in brain (i.e. NeuroMabs): for immunocytochemical-based imaging studies of protein localization in adult, developing and pathological brain samples, for biochemical analyses of subunit composition and post-translational modifications of native brain proteins, and for proteomic analyses of native brain protein networks. The NeuroMab facility was initially funded with a five-year U24 cooperative grant from NINDS and NIMH. The initial goal of the facility for this funding period is to generate a library of novel NeuroMabs against neuronal proteins, initially focusing on membrane proteins (receptors/channels/transporters), synaptic proteins, other neuronal signaling molecules, and proteins with established links to disease states. The scope of the facility was expanded with supplements from the NIH Blueprint for Neuroscience Research to include neurodevelopmental targets, the NIH Roadmap for Medical Research to include epigenetics targets, and NIH Office of Rare Diseases Research to include rare disease targets. These NeuroMabs will then be produced on a large scale and made available to the neuroscience research community on an inexpensive basis as tissue culture supernatants or purified immunoglobulin by Antibodies Inc. The UC Davis/NIH NeuroMab Facility makes NeuroMabs available directly to end users and is unable to accommodate sales to distributors for third party distribution. Note, NeuroMab antibodies are now offered through antibodiesinc.

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