期刊
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
卷 172, 期 -, 页码 26-40出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.yjmcc.2022.07.007
关键词
Calcium; Hypertrophy; Signal transduction; mAKAP; Calcineurin
资金
- National Institutes of Health [HL146111, HL126825, HL153835]
- American Heart Association [PRE34030209]
Pathological cardiac myocyte hypertrophy, which is a condition characterized by the enlargement of heart cells, is regulated by the pleiotropic Ca2+/calmodulin-dependent phosphatase calcineurin. This study reveals that the scaffold protein muscle A-Kinase Anchoring Protein beta (mAKAP beta/AKAP6 beta) organizes perinuclear signalosomes, which are responsible for localized calcium transients and the subsequent activation of calcineurin-dependent NFATc nuclear localization, leading to myocyte hypertrophy upon beta-adrenergic receptor activation. These findings demonstrate the existence of a functionally independent calcium signaling compartment in cardiac myocytes that regulates hypertrophy.
The pleiotropic Ca2+/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 Ca2+ signaling in cardiac myocytes. Here, perinuclear signalosomes organized by the scaffold protein muscle A-Kinase Anchoring Protein beta (mAKAP beta/AKAP6 beta) are shown to orchestrate local Ca2+ transients, inducing calcineurin-dependent NFATc nuclear localization and myocyte hypertrophy in response to beta-adrenergic receptor activation. Fluorescent biosensors for Ca2+ and calcineurin and protein kinase A (PKA) activity, both diffusely expressed and localized by nesprin-1 alpha to the nuclear envelope, are used to define an autonomous mAKAP beta signaling compartment in adult and neonatal rat ventricular myocytes. Notably, beta-adrenergic-stimulated perinuclear Ca2+ and PKA and CaN activity transients depended upon mAKAP beta expression, while Ca2+ elevation and PKA and CaN activity in the cytosol were mAKAP beta independent. Buffering perinuclear cAMP and Ca2+ prevented calcineurin-dependent NFATc nuclear translocation and myocyte hypertrophy, without affecting cardiac myocyte contractility. Additional findings suggest that the perinuclear Ca2+ transients were mediated by signalosome-associated ryanodine receptors regulated by local PKA phosphorylation. These results demonstrate the existence of a functionally independent Ca2+ signaling compartment in the cardiac myocyte regulating hypertrophy and provide a premise for targeting mAKAP beta signalosomes to prevent selectively cardiac hypertrophy in disease.
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