CaMKII inactivation by extracellular Ca(2+) depletion in dorsal root ganglion neurons

Cell Calcium. 2006 May;39(5):445-54. doi: 10.1016/j.ceca.2006.01.005. Epub 2006 Mar 7.


A mechanism by which Ca(2+)/CaM-dependent protein kinase (CaMKII) is autophosphorylated by changes in extracellular calcium in the absence of detectable changes in cytoplasmic [Ca(2+)] has been identified. We find that when the external Ca(2+) concentration ([Ca(2+)](O)) is lowered, Ca(2+) is released from intracellular stores to maintain a constant cytoplasmic Ca(2+) level, gradually depleting the endoplasmic Ca(2+) stores. Accompanying the store-depletion is a rapid decrease in CaMKII activity. Approximately 25% of the measured CaMKII autophosphorylation in DRG neurons in culture can be regulated by Ca(2+) flux from intracellular stores caused by manipulating [Ca(2+)](O), as shown by blocking refilling of store-operated Ca(2+)-channels with SK&F 96365, Ruthenium Red, and a partial block with Ni(2+). Blocking voltage-gated Ca(2+)-channels with either isradipine or SR 33805, had no effect on CaMKII autophosphorylation induced by restoring Ca(2+)(O) to normal after depleting the intracellular Ca(2+) stores. These results show that removal of Ca(2+)(O) has profound effects on intracellular Ca(2+) signaling and CaMKII autophosphorylation, in the absence of measurable changes in intracellular Ca(2+). These findings have wide-ranging significance, because [Ca(2+)](O) is manipulated in many experimental studies. Moreover, this explanation for the paradoxical changes in CaMKII phosphorylation in response to manipulating [Ca(2+)](O) provides a possible mechanism linking activity-dependent depletion of Ca(2+) from the synaptic cleft to a protein kinase regulating many neuronal properties.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Caffeine / metabolism
  • Caffeine / pharmacology
  • Calcium / metabolism
  • Calcium / physiology*
  • Calcium Channels / metabolism
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Cells, Cultured
  • Diffusion Chambers, Culture
  • Embryo, Mammalian / cytology
  • Embryo, Mammalian / metabolism
  • Enzyme Activation / drug effects
  • Ganglia, Spinal / cytology
  • Ganglia, Spinal / enzymology*
  • Ganglia, Spinal / metabolism
  • Immunohistochemistry
  • Intercellular Junctions / drug effects
  • Intercellular Junctions / metabolism
  • Mice
  • Neuronal Plasticity / drug effects
  • Neurons / cytology
  • Neurons / enzymology*
  • Neurons / metabolism
  • Permeability / drug effects
  • Phosphorylation
  • Signal Transduction / drug effects
  • Synaptic Transmission / drug effects
  • Time Factors


  • Calcium Channels
  • Caffeine
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Calcium