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The mAKAPbeta scaffold regulates cardiac myocyte hypertrophy via recruitment of activated calcineurin.

ABSTRACT: mAKAPbeta is the scaffold for a multimolecular signaling complex in cardiac myocytes that is required for the induction of neonatal myocyte hypertrophy. We now show that the pro-hypertrophic phosphatase calcineurin binds directly to a single site on mAKAPbeta that does not conform to any of the previously reported consensus binding sites. Calcineurin-mAKAPbeta complex formation is increased in the presence of Ca(2+)/calmodulin and in norepinephrine-stimulated primary cardiac myocytes. This binding is of functional significance because myocytes exhibit diminished norepinephrine-stimulated hypertrophy when expressing a mAKAPbeta mutant incapable of binding calcineurin. In addition to calcineurin, the transcription factor NFATc3 also associates with the mAKAPbeta scaffold in myocytes. Calcineurin bound to mAKAPbeta can dephosphorylate NFATc3 in myocytes, and expression of mAKAPbeta is required for NFAT transcriptional activity. Taken together, our results reveal the importance of regulated calcineurin binding to mAKAPbeta for the induction of cardiac myocyte hypertrophy. Furthermore, these data illustrate how scaffold proteins organizing localized signaling complexes provide the molecular architecture for signal transduction networks regulating key cellular processes.

SUBMITTER: Li J

PROVIDER: S-EPMC2813376 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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The mAKAPbeta scaffold regulates cardiac myocyte hypertrophy via recruitment of activated calcineurin.

Li Jinliang J Negro Alejandra A Lopez Johanna J Bauman Andrea L AL Henson Edward E Dodge-Kafka Kimberly K Kapiloff Michael S MS

Journal of molecular and cellular cardiology 20091031 2

mAKAPbeta is the scaffold for a multimolecular signaling complex in cardiac myocytes that is required for the induction of neonatal myocyte hypertrophy. We now show that the pro-hypertrophic phosphatase calcineurin binds directly to a single site on mAKAPbeta that does not conform to any of the previously reported consensus binding sites. Calcineurin-mAKAPbeta complex formation is increased in the presence of Ca(2+)/calmodulin and in norepinephrine-stimulated primary cardiac myocytes. This bindi ...[more]

PMID: 19883655

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Project description:BackgroundThe Ca2+/calmodulin-dependent phosphatase calcineurin is a key regulator of cardiac myocyte hypertrophy in disease. An unexplained paradox is how the β isoform of the calcineurin catalytic A-subunit (CaNAβ) is required for induction of pathological myocyte hypertrophy, despite calcineurin Aα expression in the same cells. It is unclear how the pleiotropic second messenger Ca2+ drives excitation-contraction coupling while not stimulating hypertrophy by calcineurin in the normal heart. Elucidation of the mechanisms conferring this selectivity in calcineurin signaling should reveal new strategies for targeting the phosphatase in disease.MethodsPrimary adult rat ventricular myocytes were studied for morphology and intracellular signaling. New Förster resonance energy transfer reporters were used to assay Ca2+ and calcineurin activity in living cells. Conditional gene deletion and adeno-associated virus-mediated gene delivery in the mouse were used to study calcineurin signaling after transverse aortic constriction in vivo.ResultsCIP4 (Cdc42-interacting protein 4)/TRIP10 (thyroid hormone receptor interactor 10) was identified as a new polyproline domain-dependent scaffold for CaNAβ2 by yeast 2-hybrid screen. Cardiac myocyte-specific CIP4 gene deletion in mice attenuated pressure overload-induced pathological cardiac remodeling and heart failure. Blockade of CaNAβ polyproline-dependent anchoring using a competing peptide inhibited concentric hypertrophy in cultured myocytes; disruption of anchoring in vivo using an adeno-associated virus gene therapy vector inhibited cardiac hypertrophy and improved systolic function after pressure overload. Live cell Förster resonance energy transfer biosensor imaging of cultured myocytes revealed that Ca2+ levels and calcineurin activity associated with the CIP4 compartment were increased by neurohormonal stimulation, but minimally by pacing. Conversely, Ca2+ levels and calcineurin activity detected by nonlocalized Förster resonance energy transfer sensors were induced by pacing and minimally by neurohormonal stimulation, providing functional evidence for differential intracellular compartmentation of Ca2+ and calcineurin signal transduction.ConclusionsThese results support a structural model for Ca2+ and CaNAβ compartmentation in cells based on an isoform-specific mechanism for calcineurin protein-protein interaction and localization. This mechanism provides an explanation for the specific role of CaNAβ in hypertrophy and its selective activation under conditions of pathologic stress. Disruption of CaNAβ polyproline-dependent anchoring constitutes a rational strategy for therapeutic targeting of CaNAβ-specific signaling responsible for pathological cardiac remodeling in cardiovascular disease deserving of further preclinical investigation.

Dataset Information

The mAKAPbeta scaffold regulates cardiac myocyte hypertrophy via recruitment of activated calcineurin.

Publications

The mAKAPbeta scaffold regulates cardiac myocyte hypertrophy via recruitment of activated calcineurin.

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