SERCA Activity Controls the Systolic Calcium Increase in the Nucleus of Cardiac Myocytes

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.

Recent Advances in Pharmacological and Non-Pharmacological Strategies of Cardioprotection

“…The SR has an important role in the regulating contraction-relaxation cycle in cardiac cells, acting as cytoplasmic reservoir of Ca 2+ [9]. SR sequestrates the Ca 2+ from cytosol by ATP-dependent Ca 2+ -ATPase (SERCA), especially by SERCA2 A [9].…”

“…The SR has an important role in the regulating contraction-relaxation cycle in cardiac cells, acting as cytoplasmic reservoir of Ca 2+ [9]. SR sequestrates the Ca 2+ from cytosol by ATP-dependent Ca 2+ -ATPase (SERCA), especially by SERCA2 A [9]. The excess of Ca 2+ in the cytosol is regulated by two Ca 2+ extrusion mechanisms located in plasma membrane: the Na + /Ca 2+ exchanger (NCX) and plasma membrane Ca 2+ -ATPase (PMCA) [5,9].…”

“…SR sequestrates the Ca 2+ from cytosol by ATP-dependent Ca 2+ -ATPase (SERCA), especially by SERCA2 A [9]. The excess of Ca 2+ in the cytosol is regulated by two Ca 2+ extrusion mechanisms located in plasma membrane: the Na + /Ca 2+ exchanger (NCX) and plasma membrane Ca 2+ -ATPase (PMCA) [5,9]. The NCX transports Ca 2+ from cytosol to extracellular medium (reverse mode) or from extracellular medium to cytosol (reverse mode) [9,10].…”

“…The excess of Ca 2+ in the cytosol is regulated by two Ca 2+ extrusion mechanisms located in plasma membrane: the Na + /Ca 2+ exchanger (NCX) and plasma membrane Ca 2+ -ATPase (PMCA) [5,9]. The NCX transports Ca 2+ from cytosol to extracellular medium (reverse mode) or from extracellular medium to cytosol (reverse mode) [9,10]. Thus, SERCA, NCX and PCMA play an important role in the contraction-relaxation cycle by finely regulating the [Ca 2+ ]c in cardiac cells.…”

Length-Dependent Activation of Contractility and Ca-Transient Kinetics in Auxotonically Contracting Isolated Rat Ventricular Cardiomyocytes

“…Also, the relatively small effect of SL on Ca-transient decline time supports that SERCA2a can effectively uptake the full amount of Ca 2+ released from TnC during active shortening. However, such an amount may modulate Ca 2+ signaling pathways, e.g., nucleoplasmic Ca-transient regulating (Kiess and Kockskämper, 2019) or Ca 2+ -dependent mechanisms essential for LDA in the myocardium (Neves et al, 2016).…”