A perinuclear calcium compartment regulates cardiac myocyte hypertrophy

Nuclear Calcium in Cardiac (Patho)Physiology: Small Compartment, Big Impact

“…For instance, CaN dephosphorylates cytosolic transcription factor NFAT and causes its translocation to the nucleus, where it interacts with GATA4 to mediate a hypertrophic response [ 78 ]. Importantly, recent work has demonstrated that CaN-NFAT signaling in cardiomyocytes is controlled by perinuclear signalosomes organized by the scaffold protein muscle A-Kinase anchoring protein β (mAKAPβ/AKAP6β) and is sensitive to (peri)nuclear Ca 2+ [ 10 ]. Other major targets of CaN include CRTC, FOXO1 and TFEB [ 79 ], yet their specific activation by [Ca 2+ ] nuc remains to be addressed.…”

“…To our knowledge, two genetically encoded Ca 2+ chelating proteins for selectively modulating (peri)nuclear [Ca 2+ ] have been successfully used in isolated cardiomyocytes in the past [ 10 , 153 ]. In work by Higazi et al, nuclear Ca 2+ was specifically buffered using a nuclear-targeted, red fluorescent protein-tagged form of the neuronal Ca 2+ binding protein calbindin, demonstrating that increased nuclear Ca 2+ levels are required for the induction of atrial natriuretic factor expression [ 153 ].…”

“…In work by Higazi et al, nuclear Ca 2+ was specifically buffered using a nuclear-targeted, red fluorescent protein-tagged form of the neuronal Ca 2+ binding protein calbindin, demonstrating that increased nuclear Ca 2+ levels are required for the induction of atrial natriuretic factor expression [ 153 ]. Turcotte et al used mCherry-tagged parvalbumin β-nesprin fusion protein designed to buffer Ca 2+ in the perinuclear space and showed that buffering perinuclear Ca 2+ completely inhibits isoprenaline-induced perinuclear CaN activation in both neonatal and adult myocytes [ 10 ]. Further optimization and/or knockin of such nuclear Ca 2+ regulatory proteins can be of great value for studying nucleus-restricted Ca 2+ dynamics.…”

“…Considering that the entire cardiomyocyte’s cytosol is flooded with Ca 2+ on a beat-to-beat basis, there is an obvious need for the cell to spatio-temporally distinguish between “contractile” and “signaling” Ca 2+ to properly elicit specific cellular functions [ 8 ]. This is in part achieved by the subcellular organization of cardiomyocytes in so-called microdomains that permit targeted Ca 2+ release and thereby facilitate locally restricted Ca 2+ signaling events [ 9 , 10 ]. The nucleus is considered as such distinct microdomain harboring its own nucleoplasmic Ca 2+ transient cycling machinery and signaling properties with important implications for the regulation of gene transcription [ 7 , 10 , 11 ].…”

“…This is in part achieved by the subcellular organization of cardiomyocytes in so-called microdomains that permit targeted Ca 2+ release and thereby facilitate locally restricted Ca 2+ signaling events [ 9 , 10 ]. The nucleus is considered as such distinct microdomain harboring its own nucleoplasmic Ca 2+ transient cycling machinery and signaling properties with important implications for the regulation of gene transcription [ 7 , 10 , 11 ]. While alterations in cytoplasmic Ca 2+ handling have been extensively studied and associated with the pathogenesis of cardiac remodeling, heart failure (HF) and atrial fibrillation (AF); nucleoplasmic Ca 2+ has received considerably less attention.…”