Dichotomy of Ca2+ in the heart: contraction versus intracellular signaling
Jeffery D. Molkentin
Jeffery D. Molkentin
Published March 1, 2006
Citation Information: J Clin Invest. 2006;116(3):623-626. https://doi.org/10.1172/JCI27824.
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Commentary

Dichotomy of Ca2+ in the heart: contraction versus intracellular signaling

Abstract

Ca2+ plays a pivotal role in both excitation-contraction coupling (ECC) and activation of Ca2+-dependent signaling pathways. One of the remaining questions in cardiac biology is how Ca2+-dependent signaling pathways are regulated under conditions of continual Ca2+ transients that mediate cardiac contraction during each heartbeat. Ca2+-calmodulin–dependent protein kinase II (CaMKII) activation and its ability to regulate histone deacetylase 5 (HDAC5) nuclear shuttling represent a critical Ca2+-dependent signaling circuit for controlling cardiac hypertrophy and heart failure, yet the mechanism of activation by Ca2+ is not known. In this issue of the JCI, Wu et al. convincingly demonstrate that the inositol 1,4,5-trisphosphate receptor (InsP3R) is involved in local control of Ca2+ for activating CaMKII in the nuclear envelope of adult ventricular cardiac myocytes (see the related article beginning on page 675). The overall paradigm that is demonstrated is the best example of a molecular mechanism whereby signaling is directly regulated by a local Ca2+ pool that is disparate or geometrically insensitive to cytosolic Ca2+ underlying each contractile cycle.

Authors

Jeffery D. Molkentin

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Figure 1

Schematic of potential Ca2+ sources that might be specialized to regulate reactive signaling pathways in cardiac myocytes.

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Schematic of potential Ca2+ sources that might be specialized to regulat...
(i) Some L-type Ca2+ channels (ICa,L) are not associated with the junctional complex and hence could be involved in providing a local Ca2+ signal in specific membrane-associated compartments. (ii) T-type Ca2+ channels (ICa,T) are reexpressed in hypertrophic states where they could provide Ca2+ in specific microenvironments associated with the sarcolemma to affect reactive signaling pathways. (iii) Capacitative or store-operated Ca2+ entry through transient receptor potential (TRP) channels, alone or in conjunction with (iv) InsP3R-mediated release of Ca2+ from the ER/nuclear envelope, could also provide a highly localized Ca2+ pool for controlling reactive signaling pathways in cardiac myocytes. Signaling from G protein–coupled receptors (GPCRs) activates PLC and generates InsP3, causing a perinuclear Ca2+ signal through the InsP3R, resulting in CamKII activation and HDAC5 nuclear export, as proposed by Wu et al. (2). IP3, InsP3; IP3R, InsP3R; PLN, phospholamban; NCX, Na+/Ca2+ exchanger; RyR, ryanodine receptor; CaM, calmodulin; SERCA, SR/ER Ca2+-ATPase; P, phosphate.