Abstract 298: CaMKII-Mediated Phosphorylation of InsP3R2 Activates Hypertrophic Gene Transcription
Inositol 1,4,5-triphosphosphate receptors are a family of intracellular Ca2+ channels, modulated by the ligands InsP3 and Ca2+ in response to an array of neuro-hormonal stimuli to release Ca2+ from internal stores. In cardiac myocytes, the InsP3R2, CaMKII and CaM are components of a macromolecular signalplex. However, modulation of InsP3R’s Ca2+ channel and the underlying mechanism(s) that converge and integrate nuclear hypertrophic signals to initiate transcription is not fully established. Here, we delineate the mechanistic regulation of nuclear InsP3R2’s bidirectional Ca2+ channel activity and its effect on the activation of nuclear hypertrophic signaling. We show that, endothelin-1 (ET1) stimulates elevated InsP3 induced Ca2+ release into the nucleus from perinuclear InsP3 receptors. This elevated nuclear Ca2+ release is due to CaMKIIδ mediated phosphorylation of cytoplasmic oriented InsP3R2 inhibiting Ca2+ release to the cytoplasm. This increase in nuclear Ca2+ activates Ca2+ sensitive transctiption factors thereby activating gene expression. The elevated nuclear Ca2+ and gene expression can be attenuated by CaMKII inhibitor KN-93 and InsP3R antagonist 2-ABP. We also show that, exogenous InsP3R2 was phosphorylated by both cytoplasmic (CaMKIIδC) and nuclear (CaMKIIδB) isoforms of CaMKIIδ. Intriguingly, CaMKIIδC phosphorylates endogenous InsP3R2 in cardiomyocytes more efficiently than CaMKIIδB and not by its kinase-dead derivatives. In conclusion, our findings demonstrate that, InsP3R2 mediated Ca2+ signaling integrates and vectors the GPCR activated hypertrophic signals to the nucleus triggering gene transcription underlying cardiac hypertrophy.
- © 2012 by American Heart Association, Inc.