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.
Mulholland
Patrick J
PJ
Department of Neurosciences and Center for Drug and Alcohol Programs, Medical University of South Carolina, 67 President Street, Charleston, SC 29425, USA.
Carpenter-Hyland
Ezekiel P
EP
Woodward
John J
JJ
Chandler
L Judson
LJ
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D004594:Electrophysiology; D000431:Ethanol / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D027342:Excitatory Amino Acid Transporter 2 / Q000037:antagonists & inhibitors / Q000502:physiology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D007608:Kainic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects*; D051669:Shab Potassium Channels / Q000187:drug effects*
D002492:Central Nervous System Depressants; D018691:Excitatory Amino Acid Antagonists; D027342:Excitatory Amino Acid Transporter 2; D016194:Receptors, N-Methyl-D-Aspartate; D051669:Shab Potassium Channels; C493395:Slc1a2 protein, rat; D000431:Ethanol; C020889:dihydrokainic acid; D007608:Kainic Acid