CaMKII Negatively Regulates Calcineurin–NFAT Signaling in Cardiac Myocytes

Abstract

Key Words: CaMKII Ⅲ calcineurin Ⅲ NFAT Ⅲ myocytes Ⅲ heart disease I ntermittent changes in the amplitude and duration of the systolic Ca 2ϩ transient are the principle mechanism for regulating the strength of contraction (contractility) of the heart in health. Cardiovascular diseases that cause persistent increases in systolic wall stress require sustained increases in Ca 2ϩ influx and sarcoplasmic reticulum uptake, storage and release to produce the necessary increases in [Ca 2ϩ ] required to maintain the pump function of the heart under these conditions. 1 The persistent increases in [Ca 2ϩ ] that are required to maintain cardiac pump function in pathological cardiovascular stress also activate complex signaling pathways that lead to cardiac hypertrophy, structural and functional remodeling, and cell death. 2 The signaling cascades that link changes in myocyte Ca 2ϩ to activation of hypertrophic and survival signaling are the topic of this study.Increases in myocyte [Ca 2ϩ ] activate both the type 2B Ca 2ϩ /calmodulin (CaM)-dependent phosphatase, calcineurin (Cn), and the Ca 2ϩ /CaM-dependent protein kinase II (CaMKII). Activation of these signaling pathways is linked to electric and contractile disturbances in pathological cardiac hypertrophy. 3,4 Activated Cn induces pathological hypertrophy by dephosphorylation and subsequent nuclear translocation of transcription factors associated with the NFAT family (nuclear factor of activated T cells) that activates specific hypertrophic target genes. 3,[5][6][7][8] In mice, transgenic cardiac overexpression of a constitutively active form of Cn has been shown to cause hypertrophy, mechanical dysfunction, arrhythmias, and premature death. 3,9 In larger animal models 10 and in patients, 11 increased Cn activity has been linked to structural heart disease and the development of heart failure.

Role of protein phosphorylation in excitation-contraction coupling in taurine deficient hearts

“…CaMKII regulates multiple events involved in contractile function and ventricular remodeling, including SR Ca 2ϩ leakage (8,25,47), hypertrophic gene expression and signaling (7,23), apoptosis (7,47), arrhythmias (7,8,46), and high-energy phosphate metabolism (22). Therefore, it is not surprising that CaMKII activity is elevated in most models of heart failure (50).…”

Carabin Protects Against Cardiac Hypertrophy by Blocking Calcineurin, Ras, and Ca 2+ /Calmodulin-Dependent Protein Kinase II Signaling

“…For instance, the small G protein Ras, the stress-responsive mitogen-activated protein kinases, and the Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) can cross-talk with the calcineurin signaling pathway to regulate hypertrophic processes. [9][10][11] CaMKII is known to activate the myocyte enhancer factor 2 (MEF2) on class II histone deacetylases (HDAC) phosphorylation, thereby allowing this transcription factor to induce hypertrophic gene expression. 12,13 In contrast to these growth-promoting pathways, several endogenous molecules in the heart have been shown to negatively regulate cardiac hypertrophy.…”

Silencing calcineurin A subunit reduces SERCA2 expression in cardiac myocytes

“…Furthermore, inhibition of CAMKII with KN-93 allows further increase in luciferase and SERCA2 expression, suggesting that if CN activation is not hindered by phosphorylation and inactivation by CAMKII, dephosphorylated NFAT is produced at higher rates, yielding further increase in expression and transcription of luciferase and SERCA2. In fact, constitutively active CAMKII (exogenous CAMKII overexpressed in the cytosol) was shown to downregulate CN-NFAT signaling by phosphorylation and subsequent inhibition of CN (22). CN and CAMKII are both activated by a rise of cytosolic Ca 2ϩ and therefore, under physiological conditions, CAMKII may limit and possibly optimize the extent of CN activation.…”