CaMKIIdelta isoforms differentially affect calcium handling but similarly regulate HDAC/MEF2 transcriptional
Tong Zhang1, Michael Kohlhaas, Johannes Backs
1Department of Pharmacology, University of California, San Diego, La Jolla, California 92093-0636, USA. tzhang@arenapharm.com
Abstract:
The delta(B) and delta(C) splice variants of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), which differ by the presence of a nuclear localization sequence, are both expressed in cardiomyocytes. We used transgenic (TG) mice and CaMKII expression in cardiomyocytes to test the hypothesis that the CaMKIIdelta(C) isoform regulates cytosolic Ca(2+) handling and the delta(B) isoform, which localizes to the nucleus, regulates gene transcription. Phosphorylation of CaMKII sites on the ryanodine receptor (RyR) and on phospholamban (PLB) were increased in CaMKIIdelta(C) TG. This was associated with markedly enhanced sarcoplasmic reticulum (SR) Ca(2+) spark frequency and decreased SR Ca(2+) content in cardiomyocytes. None of these parameters were altered in TG mice expressing the nuclear-targeted CaMKIIdelta(B). In contrast, cardiac expression of either CaMKIIdelta(B) or delta(C) induced transactivation of myocyte enhancer factor 2 (MEF2) gene expression and up-regulated hypertrophic marker genes. Studies using rat ventricular cardiomyocytes confirmed that CaMKIIdelta(B) and delta(C) both regulate MEF2-luciferase gene expression, increase histone deacetylase 4 (HDAC4) association with 14-3-3, and induce HDAC4 translocation from nucleus to cytoplasm, indicating that either isoform can stimulate HDAC4 phosphorylation. Finally, HDAC4 kinase activity was shown to be increased in cardiac homogenates from either CaMKIIdelta(B) or delta(C) TG mice. Thus CaMKIIdelta isoforms have similar effects on hypertrophic gene expression but disparate effects on Ca(2+) handling, suggesting distinct roles for CaMKIIdelta isoform activation in the pathogenesis of cardiac hypertrophy versus heart failure.
More Related Videos
10:28Repressing Gene Transcription by Redirecting Cellular Machinery with Chemical Epigenetic Modifiers
Published on: September 20, 2018
11:06Genome-wide Analysis of HDAC Inhibitor-mediated Modulation of microRNAs and mRNAs in B Cells Induced to Undergo Class-switch DNA Recombination and Plasma Cell Differentiation
Published on: September 20, 2017
Related Concept Videos
Calmodulin-dependent Signaling
The Ca2+-CaM complex does not have enzymatic activity by itself. Instead, the complex binds downstream target proteins, including membrane proteins or enzymes,...
Master Transcription Regulators
Structure of Cadherins
Heterochromatin
Constitutive heterochromatin: It is a highly compact region of chromatin that is mostly concentrated in the centromere and telomere. Unlike euchromatin, the amino acid at 9th...
Positive Regulator Molecules
M-Cdk Drives Transition Into Mitosis
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
M cyclin...
