Chakraborti Sajal, Das Sudip, Kar Pulak, Ghosh Biswarup, Samanta Krishna, Kolley Saurav, Ghosh Samarendranath, Roy Soumitra, Chakraborti Tapati
Department of Biochemistry and Biophysics, University of Kalyani, Kalyani, 741235, West Bengal, India.
Mol Cell Biochem. 2007 Apr;298(1-2):1-40. doi: 10.1007/s11010-006-9355-8. Epub 2006 Nov 21.
Ca(2+) is a major intracellular messenger and nature has evolved multiple mechanisms to regulate free intracellular (Ca(2+))(i) level in situ. The Ca(2+) signal inducing contraction in cardiac muscle originates from two sources. Ca(2+) enters the cell through voltage dependent Ca(2+) channels. This Ca(2+) binds to and activates Ca(2+) release channels (ryanodine receptors) of the sarcoplasmic reticulum (SR) through a Ca(2+) induced Ca(2+) release (CICR) process. Entry of Ca(2+) with each contraction requires an equal amount of Ca(2+) extrusion within a single heartbeat to maintain Ca(2+) homeostasis and to ensure relaxation. Cardiac Ca(2+) extrusion mechanisms are mainly contributed by Na(+)/Ca(2+) exchanger and ATP dependent Ca(2+) pump (Ca(2+)-ATPase). These transport systems are important determinants of (Ca(2+))(i) level and cardiac contractility. Altered intracellular Ca(2+) handling importantly contributes to impaired contractility in heart failure. Chronic hyperactivity of the beta-adrenergic signaling pathway results in PKA-hyperphosphorylation of the cardiac RyR/intracellular Ca(2+) release channels. Numerous signaling molecules have been implicated in the development of hypertrophy and failure, including the beta-adrenergic receptor, protein kinase C, Gq, and the down stream effectors such as mitogen activated protein kinases pathways, and the Ca(2+) 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 Ca(2+) handling such as RyR, SERCA2a, and PLN. Controlling these molecular functions by different agents have been found to be beneficial in some experimental conditions.
钙离子是一种主要的细胞内信使，自然界进化出了多种机制来原位调节细胞内游离钙离子（Ca²⁺）i的水平。引起心肌收缩的钙离子信号来自两个来源。钙离子通过电压依赖性钙离子通道进入细胞。这种钙离子通过钙离子诱导的钙离子释放（CICR）过程与肌浆网（SR）的钙离子释放通道（兰尼碱受体）结合并激活。每次收缩时钙离子的进入需要在单次心跳内等量的钙离子排出，以维持钙离子稳态并确保舒张。心脏钙离子排出机制主要由钠/钙交换器和ATP依赖性钙离子泵（Ca²⁺-ATPase）贡献。这些转运系统是（Ca²⁺）i水平和心脏收缩力的重要决定因素。细胞内钙离子处理的改变在心力衰竭时收缩力受损中起重要作用。β-肾上腺素能信号通路的慢性过度激活导致心脏兰尼碱受体/细胞内钙离子释放通道的蛋白激酶A过度磷酸化。许多信号分子与肥大和衰竭的发生有关，包括β-肾上腺素能受体、蛋白激酶C、Gq以及下游效应器，如丝裂原活化蛋白激酶途径和钙离子调节的磷酸酶钙调神经磷酸酶。现在已经确定了一些信号通路，它们可能是心肌细胞结构成分突变后心肌结构和功能变化的关键调节因子。心肌结构和信号转导现在正融合到一个共同的研究领域，这将导致对心脏病潜在分子机制的更全面理解。分子心脏病学的最新进展使得设想一种针对心力衰竭（HF）的新治疗方法成为可能，该方法靶向参与细胞内钙离子处理的关键分子，如兰尼碱受体、肌浆网钙离子ATP酶2a（SERCA2a）和受磷蛋白（PLN）。在一些实验条件下，发现用不同药物控制这些分子功能是有益的。
