Abstract
In cardiomyocytes, nuclear calcium is involved in regulation of transcription and, thus, remodeling. The cellular mechanisms regulating nuclear calcium, however, remain elusive. Therefore, the aim of this study was to identify and characterize the factors that regulate nuclear calcium in cardiomyocytes. We focused on the roles of (1) the cytoplasmic calcium transient (CaT), (2) the sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA), and (3) intracellular calcium stores for nuclear calcium handling. Experiments were performed on rat ventricular myocytes loaded with Fluo-4/AM. Subcellularly resolved CaTs were visualized using confocal microscopy. The cytoplasmic CaT was varied by reducing extracellular calcium (from 1.5 to 0.3 mM) or by exposure to isoprenaline (ISO, 10 nM). SERCA was blocked by thapsigargin (5 μM). There was a strict linear dependence of the nucleoplasmic CaT on the cytoplasmic CaT over a wide range of calcium concentrations. Increasing SERCA activity impaired, whereas decreasing SERCA activity augmented the systolic calcium increase in the nucleus. Perinuclear calcium store load, on the other hand, did not change with either 0.3 mM calcium or ISO and was not a decisive factor for the nucleoplasmic CaT. The results indicate, that the nucleoplasmic CaT is determined largely by the cytoplasmic CaT via diffusion of calcium through nuclear pores. They identify perinuclear SERCA activity, which limits the systolic calcium increase in the nucleus, as a novel regulator of the nuclear CaT in cardiac myocytes.
Highlights
Calcium (Ca) is a ubiquitous ion and versatile second messenger throughout all types of cells
In the line-scan image the nucleoplasmic fluorescence signal (N, Nuc, red) can be distinguished from the cytoplasmic signal (C, Cyto, black) as it appears with a delay and as it exhibits a slower decay
The fact that from perinuclear Ca stores (FRPN) was always less than from SR Ca stores (FRSR) may be explained by the preferentially passive nature of the nuclear Ca increase in systole, i.e., Ca diffusion from cytoplasm through nuclear pores, with only a small contribution from active RyR-mediated Ca release from perinuclear/nuclear envelope (NE) Ca stores (Yang and Steele, 2005; Zima et al, 2007)
Summary
Calcium (Ca) is a ubiquitous ion and versatile second messenger throughout all types of cells. It regulates a variety of important cellular processes, e.g., electrical signaling, metabolism, secretion, gene transcription and cell cycle (Berridge et al, 2000). Besides the well characterized functions of cytosolic Ca in driving the contraction-relaxation cycle in ECC, more recent studies have revealed the role of Ca in controlling gene transcription in cardiac myocytes in Nuclear Calcium Regulation a process termed excitation-transcription coupling (ETC) (Wu et al, 2006; Dewenter et al, 2017). For the adult heart it is known, that in response to neurohormonal and mechanical stress ETC can induce the reexpression of a fetal gene program, resulting in maladaptive hypertrophy and remodeling of ion channels and transporters, impairing cardiac function (Domínguez-Rodríquez et al, 2012; Dewenter et al, 2017)
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