Abstract
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.
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Acknowledgements
Thanks are due to the ICMR (New Delhi); the LSRB (DRDO, Govt. of India), the CSIR (New Delhi), DBT (Govt. of India) and the UGC (New Delhi) for partly financing our research. Thanks are also due to Prof. N.K.Ganguly (Director General, ICMR, New Delhi), Dr. Vasasntha Muthuswami (Senior Deputy Director General, ICMR, New Delhi), Dr. Vijay Kumar (Deputy Director General, ICMR, New Delhi), Dr.W.Selvamurthy (Chief Controller, DRDO, Govt. of India), Prof. Kasturi Datta (SES, Jawaharlal Nehru University, New Delhi), Dr. A. Duggal (Director, DBT, Govt. of India), Dr. Mohan Mehra (Indomedix Inc., Houston, Texas, USA) and Dr. A. Mandal (University of Arizona, Tucson, USA) for their help and interest in our research. This article is dedicated to late Prof. Nityananda Saha who died on 2nd March, 2005 while continuing as the Vice Chancellor of the University of Kalyani.
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Chakraborti, S., Das, S., Kar, P. et al. Calcium signaling phenomena in heart diseases: a perspective. Mol Cell Biochem 298, 1–40 (2007). https://doi.org/10.1007/s11010-006-9355-8
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DOI: https://doi.org/10.1007/s11010-006-9355-8