Graded regulation of the Kv2.1 potassium channel by variable phosphorylation.
Dynamic modulation of ion channels by phosphorylation underlies neuronal plasticity. The Kv2.1 potassium channel is highly phosphorylated in resting mammalian neurons. Activity-dependent Kv2.1 dephosphorylation by calcineurin induces graded hyperpolarizing shifts in voltage-dependent activation, causing suppression of neuronal excitability. Mass spectrometry-SILAC (stable isotope labeling with amino acids in cell culture) identified 16 Kv2.1 phosphorylation sites, of which 7 were dephosphorylated by calcineurin. Mutation of individual calcineurin-regulated sites to alanine produced incremental shifts mimicking dephosphorylation, whereas mutation to aspartate yielded equivalent resistance to calcineurin. Mutations at multiple sites were additive, showing that variable phosphorylation of Kv2.1 at a large number of sites allows graded activity-dependent regulation of channel gating and neuronal firing properties.
Park
Kang-Sik
KS
Department of Pharmacology, School of Medicine, University of California, Davis, CA 95616, USA.
Mohapatra
Durga P
DP
Misonou
Hiroaki
H
Trimmer
James S
JS
D000409:Alanine / Q000235:genetics / Q000378:metabolism; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001224:Aspartic Acid / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D019703:Calcineurin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002853:Chromatography, Liquid; D006801:Humans; D015640:Ion Channel Gating; D015759:Ionomycin / Q000494:pharmacology; D013058:Mass Spectrometry; D009154:Mutation; D009474:Neurons / Q000502:physiology; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D010769:Phosphothreonine / Q000378:metabolism; D017354:Point Mutation; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D012694:Serine / Q000235:genetics; D051669:Shab Potassium Channels / Q000378:metabolism*; D014162:Transfection
D011994:Recombinant Proteins; D051669:Shab Potassium Channels; D010769:Phosphothreonine; D010768:Phosphoserine; D001224:Aspartic Acid; D012694:Serine; D015759:Ionomycin; D000469:Alkaline Phosphatase; D019703:Calcineurin; D000409:Alanine; D002118:Calcium