Regulation of ion channel localization and phosphorylation by neuronal activity.
Voltage-dependent Kv2.1 K(+) channels, which mediate delayed rectifier Kv currents (I(K)), are expressed in large clusters on the somata and dendrites of principal pyramidal neurons, where they regulate neuronal excitability. Here we report activity-dependent changes in the localization and biophysical properties of Kv2.1. In the kainate model of continuous seizures in rat, we find a loss of Kv2.1 clustering in pyramidal neurons in vivo. Biochemical analysis of Kv2.1 in the brains of these rats shows a marked dephosphorylation of Kv2.1. In cultured rat hippocampal pyramidal neurons, glutamate stimulation rapidly causes dephosphorylation of Kv2.1, translocation of Kv2.1 from clusters to a more uniform localization, and a shift in the voltage-dependent activation of I(K). An influx of Ca(2+) leading to calcineurin activation is both necessary and sufficient for these effects. Our finding that neuronal activity modifies the phosphorylation state, localization and function of Kv2.1 suggests an important link between excitatory neurotransmission and the intrinsic excitability of pyramidal neurons.
Misonou
Hiroaki
H
Department of Pharmacology, School of Medicine, University of California, Davis, California 95616, USA. hmisono@ucdavis.edu
Mohapatra
Durga P
DP
Park
Eunice W
EW
Leung
Victor
V
Zhen
Dongkai
D
Misonou
Kaori
K
Anderson
Anne E
AE
Trimmer
James S
JS
D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D019256:Cadmium Chloride / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002452:Cell Count; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology; D051668:Delayed Rectifier Potassium Channels; D003712:Dendrites / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology*; D006624:Hippocampus / Q000166:cytology; D015640:Ion Channel Gating / Q000187:drug effects*; D007476:Ionophores / Q000494:pharmacology; D007608:Kainic Acid / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D009568:Nitrendipine / Q000494:pharmacology; D009570:Nitriles; D019319:Okadaic Acid / Q000494:pharmacology; D018408:Patch-Clamp Techniques / Q000379:methods; D010749:Phosphoprotein Phosphatases / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011188:Potassium / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated; D011189:Potassium Chloride / Q000494:pharmacology; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism*; D011722:Pyrethrins / Q000494:pharmacology; D051381:Rats; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology; D051669:Shab Potassium Channels; D013997:Time Factors; D014178:Translocation, Genetic / Q000187:drug effects / Q000502:physiology
D002121:Calcium Channel Blockers; D051668:Delayed Rectifier Potassium Channels; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D007476:Ionophores; C496991:Kcnb1 protein, rat; D009570:Nitriles; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011722:Pyrethrins; D051669:Shab Potassium Channels; D019319:Okadaic Acid; C017180:decamethrin; D000001:Calcimycin; D018698:Glutamic Acid; D011189:Potassium Chloride; D016572:Cyclosporine; D009568:Nitrendipine; D010749:Phosphoprotein Phosphatases; D019256:Cadmium Chloride; D011188:Potassium; D007608:Kainic Acid