title: Location matters: clarifying the concept of nuclear and cytosolic CaMKII subtypes.
abstract: BACKGROUND
  Differential effects of δ(B) and δ(C) subtypes of Ca²⁺/calmodulin-dependent protein kinase (CaMKII) on cardiomyocyte Ca²⁺ handling and survival have been suggested to result from their respective nuclear versus cytosolic localizations. CaMKIIδ subtype localization and its relationship to enzyme activation and target phosphorylation have not, however, been systematically evaluated.
  
  
  OBJECTIVE
  To determine whether CaMKIIδ subtypes are restricted to a particular subcellular location and assess the relationship of localization to enzyme activation and function.
  
  
  RESULTS
  CaMKIIδ is highly expressed in mouse heart and cardiomyocytes and concentrated in sarcoplasmic reticulum (SR)/membrane and nuclear fractions. CaMKIIδ(B) and δ(C) subtypes differ by a nuclear localization sequence, but both are present in nuclear and SR/membrane fractions. Nonselective subtype distribution is also seen in mice overexpressing CaMKIIδ(B) or δ(C), even in a CaMKIIδ null background. Fluorescently tagged CaMKIIδ(B) expressed in cardiomyocytes concentrates in nuclei whereas δ(C) concentrates in cytosol, but neither localization is exclusive. Mouse hearts exposed to phenylephrine show selective CaMKIIδ activation in the nuclear (versus SR) compartment, whereas caffeine selectively activates CaMKIIδ in SR (versus nuclei), independent of subtype. Compartmentalized activation extends to functional differences in target phosphorylation at CaMKII sites: phenylephrine increases histone deacetylase 5 phosphorylation (Ser498) but not phospholamban (Thr17), whereas the converse holds for caffeine.
  
  
  CONCLUSIONS
  These studies demonstrate that CaMKIIδ(B) and δ(C) are not exclusively restricted to the nucleus and cytosol and that spatial and functional specificity in CaMKIIδ activation is elicited by mobilization of different Ca²⁺ stores rather than by compartmentalized subtype localization.
authors: Department of Pharmacology, University of California San Diego, CA, USA.
authors: Shikha
authors: S
authors: Mishra
authors: Charles B B
authors: CB
authors: Gray
authors: Shigeki
authors: S
authors: Miyamoto
authors: Donald M
authors: DM
authors: Bers
authors: Joan Heller
authors: JH
authors: Brown
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000494:pharmacology; D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology*; D003593:Cytoplasm / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010656:Phenylephrine / Q000494:pharmacology; D010766:Phosphorylation; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology
chemical_list: D002316:Cardiotonic Agents; D010656:Phenylephrine; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium