Does contractile Ca2+ control calcineurin-NFAT signaling and pathological hypertrophy in cardiac myocytes?

Abstract

In noncontractile cells, a sustained increase in total cytoplasmic Ca(2+) concentration is typically needed to activate the intracellular protein phosphatase calcineurin, leading to dephosphorylation of the transcription factor nuclear factor of activated T cells (NFAT), its nuclear translocation, and induction of gene expression. It remains a mystery exactly how Ca(2+)-dependent signaling pathways, such as that mediated by calcineurin-NFAT, are regulated in contracting cardiac myocytes given the highly specialized manner in which Ca(2+) concentration rhythmically cycles in excitation-contraction coupling. Here, we critically review evidence that supports the hypothesis that calcineurin-NFAT signaling is regulated by contractile Ca(2+) transients in cardiac myocytes.

Fig. 1

Model of the T tubule and SR with calcium-handling proteins and its relation with β-adrenergic receptor signaling. A small amount of priming Ca²⁺ enters through the L-type Ca²⁺ channel (LTCC) to stimulate the ryanodine receptor (RyR) within the junctional complex microdomain (pink area). This induces RyR2 to open, allowing release of larger quantities of Ca²⁺ from the sarcoplasmic reticulum into the bulk cytoplasm and stimulating the myofilament proteins to induce contraction. Relaxation is produced by reestablishing a low concentration of cytosolic Ca²⁺ through closure of LTCC and RyRs, Ca²⁺ transport into the SR through SERCA, and Ca²⁺ efflux through the Na+/Ca²⁺ exchanger (NCX). β-adrenergic receptors (β-ARs) respond to catecholamines, resulting in activation of adenylyl cyclase (AC), generation of cAMP, and the activation of PKA. PKA then phosphorylates LTCC, RyR2, and PLN to enhance contractile Ca²⁺ cycling and contractility. Cardiac myocytes also contain lipid rafts rich in caveolin in the sarcolemma and T tubules that are proposed to generate local microdomains of Ca²⁺ to regulate hypertrophic signaling and activation of Ca²⁺ signaling effectors such as calcineurin.