Nuclear Calcium in Cardiac Myocytes

Abstract

Calcium (Ca2+) is a universal second messenger involved in the regulation of various cellular processes including electrical signaling, contraction, secretion, memory, gene transcription and cell death. In heart, Ca2+ governs cardiomyocytes contraction, is central in electrophysiological properties and controls major signaling pathway implicated in gene transcription. How cardiomyocytes decode Ca2+ signal to regulate gene expression without interfering with, or being controlled by “contractile” Ca2+ that floods the entire cytosol during each heart beat is still elusive. In this review we summarize recent findings on nuclear Ca2+ regulation and its downstream signaling in cardiomyocytes. We will address difficulties in reliable quantification of nuclear Ca2+ fluxes and discuss its role in the development and progression of cardiac hypertrophy and heart failure. We also point out key open questions to stimulate future work.

ER Protein Quality Control and the Unfolded Protein Response in the Heart

“…It also appears as though the calcium stored within the peri-nuclear ER of cardiac myocytes may be released into the nucleus (Fig. 2D), perhaps in coordination with contraction and each depolarization event(Ljubojevic and Bers 2015). Moreover, in contrast to SR calcium, ER calcium in cardiac myocytes can also be released in an IP 3 -dependent manner, somewhat like other cells types; this IP 3 -sensitive calcium pool may facilitate cell surface receptor regulated events in cardiac myocytes that rely on the local release of calcium that does not drive contraction (Fig.…”

Sarcoplasmic reticulum Ca2+-induced Ca2+release regulates class IIa HDAC localization in mouse embryonic cardiomyocytes

“…; Guatimosim et al. ; Bers and Shannon ; Ljubojevic and Bers ). At the heart of the E9‐11 embryo, SR Ca 2+ release is the major source of Ca 2+ and the major mechanism for pacemaking in differentiating myocytes (Rapila et al.…”

“…The nuclear envelope has been shown to be a part of a single, continuous compartment with the SR that can function as a Ca 2+ storage (Wu and Bers 2006). Furthermore, the cytosolic SR, perinuclear region, and even the nucleoplasmic reticulum have been shown to harbor both RyRs and IP 3 Rs (Ibarra et al 2014;Guatimosim et al 2008;Bers and Shannon 2013; Ljubojevic and Bers 2015). At the heart of the E9-11 embryo, SR Ca 2+ release is the major source of Ca 2+ and the major mechanism for pacemaking in differentiating myocytes Karppinen et al 2014;Korhonen et al 2008;Sasse et al 2007;Viatchenko-Karpinski et al 1999).…”

AKAP6 and phospholamban colocalize and interact in HEK‐293T cells and primary murine cardiomyocytes

“…Interestingly, Zhou et al. showed that palmitoylated PLN was identified at the perinuclear region of adult mouse cardiomyocytes, while perinuclear PLN was suggested to play a role in modulating Ca 2+ uptake and gene expression in adult mouse cardiomyocytes (Ljubojevic and Bers ; Wu et al. ; Chen et al.…”

“…However, the high localization and interaction of PLN with AKAP6 at the perinuclear region suggests that, similar to RYR2 and b2- AR activated PKA, PLN activity is regulated by AKAP6 at the level of the nucleus (Kapiloff et al 2001). Interestingly, Zhou et al 2015 showed that palmitoylated PLN was identified at the perinuclear region of adult mouse cardiomyocytes, while perinuclear PLN was suggested to play a role in modulating Ca 2+ uptake and gene expression in adult mouse cardiomyocytes (Ljubojevic and Bers 2015;Wu et al 2016;Chen et al 2018). One future approach to elucidate the specific AKAP6 and PLN downstream effects can be investigated through knocking out AKAP6 and recording Ca 2+ -cycling changes particularly at the nuclear envelope.…”