Calcium signaling phenomena in heart diseases: a perspective

Ca²⁺ is a major intracellular messenger and nature has evolved multiple mechanisms to regulate free intracellular (Ca²⁺)_i level in situ. The Ca²⁺ signal inducing contraction in cardiac muscle originates from two sources. Ca²⁺ enters the cell through voltage dependent Ca²⁺ channels. This Ca²⁺ binds to and activates Ca²⁺ release channels (ryanodine receptors) of the sarcoplasmic reticulum (SR) through a Ca²⁺ induced Ca²⁺ release (CICR) process. Entry of Ca²⁺ with each contraction requires an equal amount of Ca²⁺ extrusion within a single heartbeat to maintain Ca²⁺ homeostasis and to ensure relaxation. Cardiac Ca²⁺ extrusion mechanisms are mainly contributed by Na⁺/Ca²⁺ exchanger and ATP dependent Ca²⁺ pump (Ca²⁺-ATPase). These transport systems are important determinants of (Ca²⁺)_i level and cardiac contractility. Altered intracellular Ca²⁺ handling importantly contributes to impaired contractility in heart failure. Chronic hyperactivity of the β-adrenergic signaling pathway results in PKA-hyperphosphorylation of the cardiac RyR/intracellular Ca²⁺ release channels. Numerous signaling molecules have been implicated in the development of hypertrophy and failure, including the β-adrenergic receptor, protein kinase C, Gq, and the down stream effectors such as mitogen activated protein kinases pathways, and the Ca²⁺ regulated phosphatase calcineurin. A number of signaling pathways have now been identified that may be key regulators of changes in myocardial structure and function in response to mutations in structural components of the cardiomyocytes. Myocardial structure and signal transduction are now merging into a common field of research that will lead to a more complete understanding of the molecular mechanisms that underlie heart diseases. Recent progress in molecular cardiology makes it possible to envision a new therapeutic approach to heart failure (HF), targeting key molecules involved in intracellular Ca²⁺ handling such as RyR, SERCA2a, and PLN. Controlling these molecular functions by different agents have been found to be beneficial in some experimental conditions.