Calcium-calmodulin-dependent kinase II modulates Kv4.2 channel expression and upregulates neuronal A-type potassium currents

J Neurosci. 2004 Apr 7;24(14):3643-54. doi: 10.1523/JNEUROSCI.0154-04.2004.


Calcium-calmodulin-dependent kinase II (CaMKII) has a long history of involvement in synaptic plasticity, yet little focus has been given to potassium channels as CaMKII targets despite their importance in repolarizing EPSPs and action potentials and regulating neuronal membrane excitability. We now show that Kv4.2 acts as a substrate for CaMKII in vitro and have identified CaMKII phosphorylation sites as Ser438 and Ser459. To test whether CaMKII phosphorylation of Kv4.2 affects channel biophysics, we expressed wild-type or mutant Kv4.2 and the K(+) channel interacting protein, KChIP3, with or without a constitutively active form of CaMKII in Xenopus oocytes and measured the voltage dependence of activation and inactivation in each of these conditions. CaMKII phosphorylation had no effect on channel biophysical properties. However, we found that levels of Kv4.2 protein are increased with CaMKII phosphorylation in transfected COS cells, an effect attributable to direct channel phosphorylation based on site-directed mutagenesis studies. We also obtained corroborating physiological data showing increased surface A-type channel expression as revealed by increases in peak K(+) current amplitudes with CaMKII phosphorylation. Furthermore, endogenous A-currents in hippocampal pyramidal neurons were increased in amplitude after introduction of constitutively active CaMKII, which results in a decrease in neuronal excitability in response to current injections. Thus CaMKII can directly modulate neuronal excitability by increasing cell-surface expression of A-type K(+) channels.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / metabolism
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Calcium-Calmodulin-Dependent Protein Kinases / genetics
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Cells, Cultured
  • Chlorocebus aethiops
  • Cricetinae
  • Gene Expression Regulation / physiology*
  • Gene Transfer Techniques
  • Hippocampus / cytology
  • Kv Channel-Interacting Proteins
  • Mutagenesis, Site-Directed
  • Neurons / cytology
  • Neurons / metabolism*
  • Oocytes / metabolism
  • Patch-Clamp Techniques
  • Phosphorylation
  • Potassium / metabolism*
  • Potassium Channels / genetics
  • Potassium Channels / metabolism*
  • Potassium Channels, Voltage-Gated*
  • Pyramidal Cells / cytology
  • Pyramidal Cells / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Shal Potassium Channels
  • Up-Regulation / physiology
  • Xenopus


  • Calcium-Binding Proteins
  • Kcnd2 protein, rat
  • Kcnip3 protein, rat
  • Kv Channel-Interacting Proteins
  • Potassium Channels
  • Potassium Channels, Voltage-Gated
  • Recombinant Fusion Proteins
  • Repressor Proteins
  • Shal Potassium Channels
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Potassium