Dual role of calmodulin in autophosphorylation of multifunctional CaM kinase may underlie decoding of calcium signals

Neuron. 1994 May;12(5):943-56. doi: 10.1016/0896-6273(94)90306-9.


Autophosphorylation of multifunctional Ca2+/calmodulin-dependent protein kinase makes it Ca2+ independent by trapping bound calmodulin and by enabling the kinase to remain partially active even after calmodulin dissociates. We show that autophosphorylation is an intersubunit reaction between neighbors in the multimeric kinase which requires two molecules of calmodulin. Ca2+/calmodulin acts not only to activate the "kinase" subunit but also to present effectively the "substrate" subunit for autophosphorylation. Conversion of the kinase to the potentiated or trapped state is a cooperative process that is inefficient at low occupancy of calmodulin. Simulations show that repetitive Ca2+ pulses at limiting calmodulin lead to the recruitment of calmodulin to the holoenzyme, which further stimulates autophosphorylation and trapping. This cooperative, positive feedback loop will potentiate the response of the kinase to sequential Ca2+ transients and establish a threshold frequency at which the enzyme becomes highly active.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Brain / metabolism
  • Calcium / metabolism*
  • Calcium-Calmodulin-Dependent Protein Kinases / biosynthesis
  • Calcium-Calmodulin-Dependent Protein Kinases / isolation & purification
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Calmodulin / metabolism*
  • Cell Line
  • Chlorocebus aethiops
  • Kinetics
  • Macromolecular Substances
  • Mathematics
  • Models, Theoretical
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Oligodeoxyribonucleotides
  • Phosphorylation
  • Recombinant Proteins / biosynthesis
  • Recombinant Proteins / isolation & purification
  • Recombinant Proteins / metabolism
  • Signal Transduction*
  • Substrate Specificity
  • Swine
  • Transfection


  • Calmodulin
  • Macromolecular Substances
  • Oligodeoxyribonucleotides
  • Recombinant Proteins
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Calcium