Activity-dependent gating of CaMKII autonomous activity by Drosophila CASK

Neuron. 2006 Aug 3;51(3):327-37. doi: 10.1016/j.neuron.2006.06.020.


The ability of CaMKII to act as a molecular switch, becoming Ca(2+) independent after activation and autophosphorylation at T287, is critical for experience-dependent plasticity. Here, we show that the Drosophila homolog of CASK, also known as Camguk, can act as a gain controller on the transition to calcium-independence in vivo. Genetic loss of dCASK significantly increases synapse-specific, activity-dependent autophosphorylation of CaMKII T287. In wild-type adult animals, simple and complex sensory stimuli cause region-specific increases in pT287. dCASK-deficient adults have a reduced dynamic range for activity-dependent T287 phosphorylation and have circuit-level defects that result in inappropriate activation of the kinase. dCASK control of the CaMKII switch occurs via its ability to induce autophosphorylation of T306 in the kinase's CaM binding domain. Phosphorylation of T306 blocks Ca(2+)/CaM binding, lowering the probability of intersubunit T287 phosphorylation, which requires CaM binding to both the substrate and catalytic subunits. dCASK is the first CaMKII-interacting protein other than CaM found to regulate this plasticity-controlling molecular switch.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Calcium-Calmodulin-Dependent Protein Kinases / genetics
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Calcium-Calmodulin-Dependent Protein Kinases / physiology*
  • Drosophila
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism
  • Drosophila Proteins / physiology*
  • Electric Stimulation / methods
  • Enzyme Activation / physiology
  • Female
  • Guanylate Kinases
  • Ion Channel Gating / physiology*
  • Male
  • Phosphorylation
  • Retina / enzymology
  • Synapses / enzymology
  • Synapses / genetics


  • Drosophila Proteins
  • CASK kinases
  • CASK protein, Drosophila
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Guanylate Kinases