title: CaMKII inactivation by extracellular Ca(2+) depletion in dorsal root ganglion neurons.
abstract: 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.
authors.affiliation: Nervous System Development and Plasticity Section, National Institutes of Health, NICHD, Bldg. 35, Room 2A211, MSC 3713, 35 Lincoln Drive, Bethesda, MD 20892, USA.
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Cohen
authors.forename: R Douglas
authors.initials: RD
authors.lastname: Fields
mesh_terms: D000818:Animals; D002110:Caffeine / Q000378:metabolism / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism / Q000502:physiology*; D015220:Calcium Channels / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002478:Cells, Cultured; D015194:Diffusion Chambers, Culture; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005727:Ganglia, Spinal / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D007150:Immunohistochemistry; D007365:Intercellular Junctions / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009473:Neuronal Plasticity / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D010539:Permeability / Q000187:drug effects; D010766:Phosphorylation; D015398:Signal Transduction / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects; D013997:Time Factors
chemical_list: D015220:Calcium Channels; D002110:Caffeine; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002118:Calcium