Cardiac type 2 inositol 1,4,5-trisphosphate receptor: Interaction and modulation by calcium/calmodulin-dependent protein kinase II

Dan J. Bare, Claudia S. Kettlun, Mei Liang, Donald M Bers, Gregory A. Mignery

Research output: Contribution to journalArticlepeer-review

146 Scopus citations

Abstract

The type 2 inositol 1,4,5-trisphosphate receptor (InsP3R2) was identified previously as the predominant isoform in cardiac ventricular myocytes. Here we reported the subcellular localization of InsP3R2 to the cardiomyocyte nuclear envelope (NE). The other major known endo/sarcoplasmic reticulum calcium-release channel (ryanodine receptor) was not localized to the NE, indicating functional segregation of these channels and possibly a unique role for InsP3R2 in regulating nuclear calcium dynamics. Immunoprecipitation experiments revealed that the NE InsP 3R2 associates with Ca2+/calmodulin-dependent protein kinase IIδ (CaMKIIδ), the major isoform expressed in cardiac myocytes. Recombinant InsP3R2 and CaMKIIδB also co-immunoprecipitated after co-expression in COS-1 cells. Additionally, the amino-terminal 1078 amino acids of the InsP3R2 were sufficient for interaction with CaMKIIδB and associated upon mixing following separate expression. CaMKII can also phosphorylate InsP3R2, as demonstrated by 32P labeling. Incorporation of CaMKII-treated InsP3R2 into planar lipid bilayers revealed that InsP 3-mediated channel open probability is significantly reduced (∼11 times) by phosphorylation via CaMKII. We concluded that the InsP3R2 and CaMKIIδ likely represent two central components of a multiprotein signaling complex, and this raises the possibility that calcium release via InsP3R2 in the myocyte NE may activate local CaMKII signaling, which may feedback on InsP3R2 function.

Original languageEnglish (US)
Pages (from-to)15912-15920
Number of pages9
JournalJournal of Biological Chemistry
Volume280
Issue number16
DOIs
StatePublished - Apr 22 2005
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry

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