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Science 313 (5789): 976-979

Copyright © 2006 by the American Association for the Advancement of Science

Graded Regulation of the Kv2.1 Potassium Channel by Variable Phosphorylation

Kang-Sik Park,* Durga P. Mohapatra,* Hiroaki Misonou, James S. Trimmer{dagger}

Abstract: 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.

Department of Pharmacology, School of Medicine, University of California, Davis, CA 95616, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed at the Department of Pharmacology, School of Medicine 3502 GBSF, 451 East Health Sciences Drive, University of California, Davis, CA 95616, USA. E-mail: jtrimmer{at}ucdavis.edu


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