Decoding Ca2+ signals to the nucleus by multifunctional CaM kinase.
Multifunctional Ca2+/calmodulin-dependent protein kinase (CaM kinase) is one of the major protein kinases coordinating cellular responses to neurotransmitters and hormones. CaM kinase transduces changes in intracellular free Ca2+ into changes in the phosphorylation state and activity of target proteins involved in neurotransmitter synthesis and release, neuronal plasticity and gene expression. Structure/function analyses of the kinase reveal the kinase is kept inactive in its basal state by a regulatory domain that is displaced by the binding of Ca2+/calmodulin. Once activated by Ca2+/calmodulin, autophosphorylation occurs if a pair of proximate subunits of the decameric kinase have calmodulin bound. The frequency of Ca2+ oscillations or spikes may be decoded by CaM kinase via this autophosphorylation. Calmodulin is essentially trapped by autophosphorylation which converts CaM kinase into a high affinity calmodulin-binding protein. Repetitive stimulation of the kinase may promote recruitment of calmodulin to the kinase so that it becomes increasingly active with each stimulus in a frequency-dependent manner. The association domain at the C-terminal end of CaM kinase contains a variable region that targets isoforms of the kinase to the nucleus or cytoskeleton and assembles the kinase into a decameric structure. Alternative splicing introduces a short nuclear localization signal that targets transfected kinase to the nucleus where it may regulate nuclear functions. The regulatory properties of CaM kinase provide for molecular potentiation of Ca2+ signals and frequency detection whereas its association domain should enable it to decode such Ca2+ fluctuations in the nucleus.
Schulman
H
H
Department of Neurobiology, Stanford University School of Medicine, CA 94305-5401, USA.
Heist
K
K
Srinivasan
M
M
D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000502:physiology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology*; D002467:Cell Nucleus / Q000502:physiology*; D006801:Humans; D008969:Molecular Sequence Data; D015398:Signal Transduction / Q000502:physiology*
D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002118:Calcium