A perinuclear calcium compartment regulates cardiac myocyte hypertrophy.

The pleiotropic Ca ²⁺ /calmodulin-dependent phosphatase calcineurin is a key regulator of pathological cardiac myocyte hypertrophy. The selective activation of hypertrophic calcineurin signaling under stress conditions has been attributed to compartmentation of Ca ²⁺ signaling in cardiac myocytes. Here, perinuclear signalosomes organized by the scaffold protein muscle A-Kinase Anchoring Protein β (mAKAPβ/AKAP6β) are shown to orchestrate local Ca ²⁺ transients, inducing calcineurin-dependent NFATc nuclear localization and myocyte hypertrophy in response to β-adrenergic receptor activation. Fluorescent biosensors for Ca ²⁺ and calcineurin and protein kinase A (PKA) activity, both diffusely expressed and localized by nesprin-1α to the nuclear envelope, are used to define an autonomous mAKAPβ signaling compartment in adult and neonatal rat ventricular myocytes. Notably, β-adrenergic-stimulated perinuclear Ca ²⁺ and PKA and CaN activity transients depended upon mAKAPβ expression, while Ca ²⁺ elevation and PKA and CaN activity in the cytosol were mAKAPβ independent. Buffering perinuclear cAMP and Ca ²⁺ prevented calcineurin-dependent NFATc nuclear translocation and myocyte hypertrophy, without affecting cardiac myocyte contractility. Additional findings suggest that the perinuclear Ca ²⁺ transients were mediated by signalosome-associated ryanodine receptors regulated by local PKA phosphorylation. These results demonstrate the existence of a functionally independent Ca ²⁺ signaling compartment in the cardiac myocyte regulating hypertrophy and provide a premise for targeting mAKAPβ signalosomes to prevent selectively cardiac hypertrophy in disease.
Competing Interests: Declaration of Competing Interest Dr. Kapiloff is an inventor of patent-protected intellectual property concerning the targeting of mAKAPβ signalosomes for the treatment of heart failure, by which he and Stanford University may gain royalties from future commercialization. Dr. Kapiloff holds equity in Anchored RSK3 Inhibitors, LLC, and Cardiac RSK3 Inhibitors, LLC, companies interested in developing mAKAP signalosome-targeted therapies.
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