Calcium/calmodulin-dependent protein kinase type II subunit delta
protein phosphorylation
Nuclear calcium/calmodulin-dependent protein kinase IIdelta preferentially transmits signals to histone deacetylase 4 in cardiac cells.
Class II histone deacetylases (HDACs) act as repressors of cardiac hypertrophy, an adaptative response of the heart characterized by a reprogramming of fetal cardiac genes. Prolonged hypertrophy often leads to dilated cardiomyopathy and heart failure. Upstream endogenous regulators of class II HDACs that regulate hypertrophic growth are just beginning to emerge. Here we demonstrate that the delta B isoform of calcium/calmodulin-dependent protein kinase II (CaMKIIdeltaB), known to promote cardiac hypertrophy, transmits signals specifically to HDAC4 but not other class II HDACs. CaMKIIdeltaB efficiently phosphorylates both a glutathione S-transferase (GST)-HDAC4 fragment spanning amino acids 207-311 and full-length FLAG-HDAC4 but not the equivalents in HDAC5. Although previous studies in skeletal muscle cells have shown that HDAC4 lacking serine 246 cannot be phosphorylated by CaMKI/IV, a similar mutant is still phosphorylated by CaMKIIdeltaB. Importantly, mutation of serine 210 to alanine totally abolishes phosphorylation of the GST fragment and significantly reduces phosphorylation of full-length HDAC by CaMKIIdeltaB. RNA interference knockdown of CaMKIIdeltaB prevents the effects of hypertrophic stimuli. Overexpression of CaMKIIdeltaB in primary neonatal cardiomyocytes increases the activity of the Mef2 transcription factor and completely rescues HDAC4-mediated repression of MEF2 but only partially rescues inhibition by HDAC5 or the HDAC4 S210A mutant. CaMKIIdeltaB strongly interacts with HDAC4 in cells but not with HDAC5. These results demonstrate that CaMKIIdeltaB preferentially targets HDAC4, and this involves serine 210. These findings identify HDAC4 as a specific downstream substrate of CaMKIIdeltaB in cardiac cells and have broad applications for the signaling pathways leading to cardiac hypertrophy and heart failure.