Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

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}

Comparative analysis of Erk phosphorylation suggests a mixed strategy for measuring phospho-form distributions.
S. Prabakaran, R. A. Everley, I. Landrieu, J.-M. Wieruszeski, G. Lippens, H. Steen, and J. Gunawardena (2014)
Mol Syst Biol 7, 482
   Abstract »    Full Text »    PDF »
Cyclin E1 Regulates Kv2.1 Channel Phosphorylation and Localization in Neuronal Ischemia.
N. H. Shah, A. J. Schulien, K. Clemens, T. D. Aizenman, T. M. Hageman, Z. P. Wills, and E. Aizenman (2014)
J. Neurosci. 34, 4326-4331
   Abstract »    Full Text »    PDF »
Calcineurin inhibitor induces pain hypersensitivity by potentiating pre- and postsynaptic NMDA receptor activity in spinal cords.
S.-R. Chen, Y.-M. Hu, H. Chen, and H.-L. Pan (2014)
J. Physiol. 592, 215-227
   Abstract »    Full Text »    PDF »
Resveratrol inhibits Kv2.2 currents through the estrogen receptor GPR30-mediated PKC pathway.
W.-H. Dong, J.-C. Chen, Y.-L. He, J.-J. Xu, and Y.-A. Mei (2013)
Am J Physiol Cell Physiol 305, C547-C557
   Abstract »    Full Text »    PDF »
Post-translational modifications of the cardiac Na channel: contribution of CaMKII-dependent phosphorylation to acquired arrhythmias.
A. W. Herren, D. M. Bers, and E. Grandi (2013)
Am J Physiol Heart Circ Physiol 305, H431-H445
   Abstract »    Full Text »    PDF »
Mutation of Light-dependent Phosphorylation Sites of the Drosophila Transient Receptor Potential-like (TRPL) Ion Channel Affects Its Subcellular Localization and Stability.
A. C. Cerny, T. Oberacker, J. Pfannstiel, S. Weigold, C. Will, and A. Huber (2013)
J. Biol. Chem. 288, 15600-15613
   Abstract »    Full Text »    PDF »
Regulation of Kv2.1 K+ Conductance by Cell Surface Channel Density.
P. D. Fox, R. J. Loftus, and M. M. Tamkun (2013)
J. Neurosci. 33, 1259-1270
   Abstract »    Full Text »    PDF »
Functional Analysis of Missense Mutations in Kv8.2 Causing Cone Dystrophy with Supernormal Rod Electroretinogram.
K. E. Smith, S. E. Wilkie, J. T. Tebbs-Warner, B. J. Jarvis, L. Gallasch, M. Stocker, and D. M. Hunt (2012)
J. Biol. Chem. 287, 43972-43983
   Abstract »    Full Text »    PDF »
Distinct Modifications in Kv2.1 Channel via Chemokine Receptor CXCR4 Regulate Neuronal Survival-Death Dynamics.
A. J. Shepherd, L. Loo, R. P. Gupte, A. D. Mickle, and D. P. Mohapatra (2012)
J. Neurosci. 32, 17725-17739
   Abstract »    Full Text »    PDF »
The complex actions of sumatriptan on rat dural afferents.
A. M. Harriott, N. N. Scheff, and M. S. Gold (2012)
Cephalalgia 32, 738-749
   Abstract »    Full Text »    PDF »
Ca2+/Calmodulin-dependent Protein Kinase II (CaMKII) Regulates Cardiac Sodium Channel NaV1.5 Gating by Multiple Phosphorylation Sites.
N. M. Ashpole, A. W. Herren, K. S. Ginsburg, J. D. Brogan, D. E. Johnson, T. R. Cummins, D. M. Bers, and A. Hudmon (2012)
J. Biol. Chem. 287, 19856-19869
   Abstract »    Full Text »    PDF »
Distinct Dendritic Spine and Nuclear Phases of Calcineurin Activation after Exposure to Amyloid-{beta} Revealed by a Novel Fluorescence Resonance Energy Transfer Assay.
H.-Y. Wu, E. Hudry, T. Hashimoto, K. Uemura, Z.-Y. Fan, O. Berezovska, C. L. Grosskreutz, B. J. Bacskai, and B. T. Hyman (2012)
J. Neurosci. 32, 5298-5309
   Abstract »    Full Text »    PDF »
Electrically Silent Kv Subunits: Their Molecular and Functional Characteristics.
E. Bocksteins and D. J. Snyders (2012)
Physiology 27, 73-84
   Abstract »    Full Text »    PDF »
Group VIA PLA2 (iPLA2{beta}) Is Activated Upstream of p38 Mitogen-activated Protein Kinase (MAPK) in Pancreatic Islet {beta}-Cell Signaling.
H. Song, M. Wohltmann, M. Tan, S. Bao, J. H. Ladenson, and J. Turk (2012)
J. Biol. Chem. 287, 5528-5541
   Abstract »    Full Text »    PDF »
Phosphorylation of the voltage-gated potassium channel Kv2.1 by AMP-activated protein kinase regulates membrane excitability.
N. Ikematsu, M. L. Dallas, F. A. Ross, R. W. Lewis, J. N. Rafferty, J. A. David, R. Suman, C. Peers, D. G. Hardie, and A. M. Evans (2011)
PNAS 108, 18132-18137
   Abstract »    Full Text »    PDF »
Can selectivity be functionally modulated in ion channels?.
R. Fesce, L. Forti, A. Polenghi, A. Locarno, R. Canella, O. Sacchi, and M. L. Rossi (2011)
J. Gen. Physiol. 138, 367-370
   Full Text »    PDF »
Activity-dependent Phosphorylation of Neuronal Kv2.1 Potassium Channels by CDK5.
O. Cerda and J. S. Trimmer (2011)
J. Biol. Chem. 286, 28738-28748
   Abstract »    Full Text »    PDF »
Sequential Phosphorylation of Smoothened Transduces Graded Hedgehog Signaling.
Y. Su, J. K. Ospina, J. Zhang, A. P. Michelson, A. M. Schoen, and A. J. Zhu (2011)
Science Signaling 4, ra43
   Abstract »    Full Text »    PDF »
Carbon monoxide protects against oxidant-induced apoptosis via inhibition of Kv2.1.
M. L. Dallas, J. P. Boyle, C. J. Milligan, R. Sayer, T. L. Kerrigan, C. McKinstry, P. Lu, J. Mankouri, M. Harris, J. L. Scragg, et al. (2011)
FASEB J 25, 1519-1530
   Abstract »    Full Text »    PDF »
SUMO modification of cell surface Kv2.1 potassium channels regulates the activity of rat hippocampal neurons.
L. D. Plant, E. J. Dowdell, I. S. Dementieva, J. D. Marks, and S. A. N. Goldstein (2011)
J. Gen. Physiol. 137, 441-454
   Abstract »    Full Text »    PDF »
A SUMO-Phospho tag team for wrestling with potassium channel gating.
D. Mandikian, O. Cerda, J. T. Sack, and J. S. Trimmer (2011)
J. Gen. Physiol. 137, 435-439
   Full Text »    PDF »
Cdk-mediated phosphorylation of the Kv{beta}2 auxiliary subunit regulates Kv1 channel axonal targeting.
H. Vacher, J.-W. Yang, O. Cerda, A. Autillo-Touati, B. Dargent, and J. S. Trimmer (2011)
J. Cell Biol. 192, 813-824
   Abstract »    Full Text »    PDF »
AKAP79/150 Impacts Intrinsic Excitability of Hippocampal Neurons through Phospho-Regulation of A-type K+ Channel Trafficking.
L. Lin, W. Sun, F. Kung, M. L. Dell'Acqua, and D. A. Hoffman (2011)
J. Neurosci. 31, 1323-1332
   Abstract »    Full Text »    PDF »
Mining recent brain proteomic databases for ion channel phosphosite nuggets.
O. Cerda, J.-H. Baek, and J. S. Trimmer (2011)
J. Gen. Physiol. 137, 3-16
   Abstract »    Full Text »    PDF »
Graded enhancement of p53 binding to CREB-binding protein (CBP) by multisite phosphorylation.
C. W. Lee, J. C. Ferreon, A. C. M. Ferreon, M. Arai, and P. E. Wright (2010)
PNAS 107, 19290-19295
   Abstract »    Full Text »    PDF »
Going native: voltage-gated potassium channels controlling neuronal excitability.
J. Johnston, I. D. Forsythe, and C. Kopp-Scheinpflug (2010)
J. Physiol. 588, 3187-3200
   Abstract »    Full Text »    PDF »
Localization-dependent activity of the Kv2.1 delayed-rectifier K+ channel.
K. M. S. O'Connell, R. Loftus, and M. M. Tamkun (2010)
PNAS 107, 12351-12356
   Abstract »    Full Text »    PDF »
Formation of Heteromeric Kv2 Channels in Mammalian Brain Neurons.
Y. Kihira, T. O. Hermanstyne, and H. Misonou (2010)
J. Biol. Chem. 285, 15048-15055
   Abstract »    Full Text »    PDF »
Downregulation of Dendritic HCN Channel Gating in Epilepsy Is Mediated by Altered Phosphorylation Signaling.
S. Jung, J. B. Bullis, I. H. Lau, T. D. Jones, L. N. Warner, and N. P. Poolos (2010)
J. Neurosci. 30, 6678-6688
   Abstract »    Full Text »    PDF »
Light-dependent Phosphorylation of the Drosophila Transient Receptor Potential Ion Channel.
O. Voolstra, K. Beck, C. Oberegelsbacher, J. Pfannstiel, and A. Huber (2010)
J. Biol. Chem. 285, 14275-14284
   Abstract »    Full Text »    PDF »
Regulation of Kv channel expression and neuronal excitability in rat medial nucleus of the trapezoid body maintained in organotypic culture.
H. Tong, J. R. Steinert, S. W. Robinson, T. Chernova, D. J. Read, D. L. Oliver, and I. D. Forsythe (2010)
J. Physiol. 588, 1451-1468
   Abstract »    Full Text »    PDF »
ERK1/2 Mitogen-Activated Protein Kinase Phosphorylates Sodium Channel Nav1.7 and Alters Its Gating Properties.
S. Stamboulian, J.-S. Choi, H.-S. Ahn, Y.-W. Chang, L. Tyrrell, J. A. Black, S. G. Waxman, and S. D. Dib-Hajj (2010)
J. Neurosci. 30, 1637-1647
   Abstract »    Full Text »    PDF »
Homeostatic Regulation of Neuronal Excitability by K+ Channels in Normal and Diseased Brains.
H. Misonou (2010)
Neuroscientist 16, 51-64
   Abstract »    PDF »
Rearrangements in the Relative Orientation of Cytoplasmic Domains Induced by a Membrane-anchored Protein Mediate Modulations in Kv Channel Gating.
A. Lvov, D. Greitzer, S. Berlin, D. Chikvashvili, S. Tsuk, I. Lotan, and I. Michaelevski (2009)
J. Biol. Chem. 284, 28276-28291
   Abstract »    Full Text »    PDF »
Suppression of a pro-apoptotic K+ channel as a mechanism for hepatitis C virus persistence.
J. Mankouri, M. L. Dallas, M. E. Hughes, S. D. C. Griffin, A. Macdonald, C. Peers, and M. Harris (2009)
PNAS 106, 15903-15908
   Abstract »    Full Text »    PDF »
Regulation of apoptotic potassium currents by coordinated zinc-dependent signalling.
P. T. Redman, K. A. Hartnett, M. A. Aras, E. S. Levitan, and E. Aizenman (2009)
J. Physiol. 587, 4393-4404
   Abstract »    Full Text »    PDF »
Role of Ca2+ in injury-induced changes in sodium current in rat skeletal muscle.
G. N. Filatov, M. J. Pinter, and M. M. Rich (2009)
Am J Physiol Cell Physiol 297, C352-C359
   Abstract »    Full Text »    PDF »
Kv2.1 and silent Kv subunits underlie the delayed rectifier K+ current in cultured small mouse DRG neurons.
E. Bocksteins, A. L. Raes, G. Van de Vijver, T. Bruyns, P.-P. Van Bogaert, and D. J. Snyders (2009)
Am J Physiol Cell Physiol 296, C1271-C1278
   Abstract »    Full Text »    PDF »
Protein kinase CK2 contributes to the organization of sodium channels in axonal membranes by regulating their interactions with ankyrin G.
A. Brechet, M.-P. Fache, A. Brachet, G. Ferracci, A. Baude, M. Irondelle, S. Pereira, C. Leterrier, and B. Dargent (2008)
J. Cell Biol. 183, 1101-1114
   Abstract »    Full Text »    PDF »
Time-Dependent Block of Ultrarapid-Delayed Rectifier K+ Currents by Aconitine, a Potent Cardiotoxin, in Heart-Derived H9c2 Myoblasts and in Neonatal Rat Ventricular Myocytes.
Y.-J. Wang, B.-S. Chen, M.-W. Lin, A.-A. Lin, H. Peng, R. J. Sung, and S.-N. Wu (2008)
Toxicol. Sci. 106, 454-463
   Abstract »    Full Text »    PDF »
Profiling the Phospho-status of the BKCa Channel {alpha} Subunit in Rat Brain Reveals Unexpected Patterns and Complexity.
J. Yan, J. V. Olsen, K.-S. Park, W. Li, W. Bildl, U. Schulte, R. W. Aldrich, B. Fakler, and J. S. Trimmer (2008)
Mol. Cell. Proteomics 7, 2188-2198
   Abstract »    Full Text »    PDF »
Quantitative proteomic analysis of primary neurons reveals diverse changes in synaptic protein content in fmr1 knockout mice.
L. Liao, S. K. Park, T. Xu, P. Vanderklish, and J. R. Yates III (2008)
PNAS 105, 15281-15286
   Abstract »    Full Text »    PDF »
Chemical and Pathway Proteomics: Powerful Tools for Oncology Drug Discovery and Personalized Health Care.
U. Kruse, M. Bantscheff, G. Drewes, and C. Hopf (2008)
Mol. Cell. Proteomics 7, 1887-1901
   Abstract »    Full Text »    PDF »
Glutamate Transporters Regulate Extrasynaptic NMDA Receptor Modulation of Kv2.1 Potassium Channels.
P. J. Mulholland, E. P. Carpenter-Hyland, M. C. Hearing, H. C. Becker, J. J. Woodward, and L. J. Chandler (2008)
J. Neurosci. 28, 8801-8809
   Abstract »    Full Text »    PDF »
Physiology and Pathophysiology of Potassium Channels in Gastrointestinal Epithelia.
D. Heitzmann and R. Warth (2008)
Physiol Rev 88, 1119-1182
   Abstract »    Full Text »    PDF »
Interdomain Cytoplasmic Interactions Govern the Intracellular Trafficking, Gating, and Modulation of the Kv2.1 Channel.
D. P. Mohapatra, D. F. Siino, and J. S. Trimmer (2008)
J. Neurosci. 28, 4982-4994
   Abstract »    Full Text »    PDF »
Repetitive Firing Triggers Clustering of Kv2.1 Potassium Channels in Aplysia Neurons.
Y. Zhang, S. E. McKay, B. Bewley, and L. K. Kaczmarek (2008)
J. Biol. Chem. 283, 10632-10641
   Abstract »    Full Text »    PDF »
Dendritic Excitability and Synaptic Plasticity.
P. J. Sjostrom, E. A. Rancz, A. Roth, and M. Hausser (2008)
Physiol Rev 88, 769-840
   Abstract »    Full Text »    PDF »
Potassium Channel Phosphorylation in Excitable Cells: Providing Dynamic Functional Variability to a Diverse Family of Ion Channels.
K.-S. Park, J.-W. Yang, E. Seikel, and J. S. Trimmer (2008)
Physiology 23, 49-57
   Abstract »    Full Text »    PDF »
Inhibition of Delayed Rectifier Potassium Channels and Induction of Arrhythmia: A NOVEL EFFECT OF CELECOXIB AND THE MECHANISM UNDERLYING IT.
R. V. Frolov, I. G. Berim, and S. Singh (2008)
J. Biol. Chem. 283, 1518-1524
   Abstract »    Full Text »    PDF »
Sarcoplasmic reticulum Ca2+ leak in heart failure: mere observation or functional relevance?.
C. H. George (2008)
Cardiovasc Res 77, 302-314
   Abstract »    Full Text »    PDF »
Identification of in Vivo Phosphorylation Sites and Their Functional Significance in the Sodium Iodide Symporter.
D. D. Vadysirisack, E. S.-W. Chen, Z. Zhang, M.-D. Tsai, G.-D. Chang, and S. M. Jhiang (2007)
J. Biol. Chem. 282, 36820-36828
   Abstract »    Full Text »    PDF »
Trafficking-dependent phosphorylation of Kv1.2 regulates voltage-gated potassium channel cell surface expression.
J.-W. Yang, H. Vacher, K.-S. Park, E. Clark, and J. S. Trimmer (2007)
PNAS 104, 20055-20060
   Abstract »    Full Text »    PDF »
The voltage-gated Na+ channel NaVBP co-localizes with methyl-accepting chemotaxis protein at cell poles of alkaliphilic Bacillus pseudofirmus OF4.
S. Fujinami, T. Sato, J. S. Trimmer, B. W. Spiller, D. E. Clapham, T. A. Krulwich, I. Kawagishi, and M. Ito (2007)
Microbiology 153, 4027-4038
   Abstract »    Full Text »    PDF »
Progressive Dendritic HCN Channelopathy during Epileptogenesis in the Rat Pilocarpine Model of Epilepsy.
S. Jung, T. D. Jones, J. N. Lugo Jr, A. H. Sheerin, J. W. Miller, R. D'Ambrosio, A. E. Anderson, and N. P. Poolos (2007)
J. Neurosci. 27, 13012-13021
   Abstract »    Full Text »    PDF »
The Surprising Catch of a Voltage-Gated Potassium Channel in a Neuronal SNARE.
D. P. Mohapatra, H. Vacher, and J. S. Trimmer (2007)
Sci. STKE 2007, pe37
   Abstract »    Full Text »    PDF »
Firing Properties of GABAergic Versus Non-GABAergic Vestibular Nucleus Neurons Conferred by a Differential Balance of Potassium Currents.
A. H. Gittis and S. du Lac (2007)
J Neurophysiol 97, 3986-3996
   Abstract »    Full Text »    PDF »
Apoptotic surge of potassium currents is mediated by p38 phosphorylation of Kv2.1.
P. T. Redman, K. He, K. A. Hartnett, B. S. Jefferson, L. Hu, P. A. Rosenberg, E. S. Levitan, and E. Aizenman (2007)
PNAS 104, 3568-3573
   Abstract »    Full Text »    PDF »
Bidirectional Activity-Dependent Regulation of Neuronal Ion Channel Phosphorylation.
H. Misonou, M. Menegola, D. P. Mohapatra, L. K. Guy, K.-S. Park, and J. S. Trimmer (2006)
J. Neurosci. 26, 13505-13514
   Abstract »    Full Text »    PDF »
Highlights From The Literature.
Physiology 21, 374-379
   Full Text »    PDF »
Cellular Excitability and the Regulation of Functional Neuronal Identity: From Gene Expression to Neuromodulation.
D. J. Schulz, R. A. Baines, C. M. Hempel, L. Li, B. Liss, and H. Misonou (2006)
J. Neurosci. 26, 10362-10367
   Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882