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Subcellular localization and activation of CaMKII delta splice variants
Author(s) -
Mishra Shikha,
Zhang Tong,
Brown Joan Heller
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.772.4
Subject(s) - subcellular localization , gene isoform , nuclear localization sequence , phosphorylation , cell fractionation , genetically modified mouse , transgene , microbiology and biotechnology , splice , cytoplasm , nucleus , immunostaining , biology , chemistry , biochemistry , gene , immunohistochemistry , immunology , membrane
Ca2+/Calmodulin dependent protein kinase II delta (CaMKII D) is the predominant isoform in the heart. There are two splice variants, deltaB (DB) and deltaC (DC) which differ only by a nuclear localization sequence in DB. We previously reported that cardiac DB and DC transgenic (TG) mice both develop hypertrophy but only DC TG mice show altered Ca handling and transition to heart failure. The inclusion of an NLS and our findings from immunostaining suggest distinct localization of DB and DC which could affect the targets and consequences of transgene expression. Surprisingly, subcellular fractionation of hearts from DB and DC mice revealed that CaMKII D localization is not distinct. In DB mice, more than 50% of total CaMKII D was located outside the nucleus, and in DC mice, almost 25% of total CaMKII is in the nucleus. Since CaMKII is multimeric, we hypothesized that this apparent “mislocalization” could reflect formation of heteromultimers. Accordingly, we crossed DB and DC TG mice with recently generated CaMKII D null mice. In the single isoform TG mice, subcellular fractionation revealed that the distribution of DB and DC was nearly identical to that described above. Further studies using these mice are underway to determine whether there is a differential activation of CaMKII DB and DC at distinct subcellular sites and how this dictates target phosphorylation, cellular responses and heart failure progression.