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.

Figure 1

Schematic of potential Ca²⁺ sources that might be specialized to regulate reactive signaling pathways in cardiac myocytes. (i) Some L-type Ca²⁺ channels (I_Ca,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 (I_Ca,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.