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Recent role of calcium in cell signaling

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  • 1. Recent Role of Calcium in cell signaling
  • 2. Introduction: In the furnaces of the stars the elements evolved from hydrogen. When oxygen and neon captured successive α particles, the element calcium was born. Roughly 10 billion years later, cell membranes began to parse the world by charge, temporarily and locally defying relentless entropy. To adapt to changing environments, cells must signal, and signaling requires messengers whose concentration varies with time. Filling this role, calcium ions (Ca2+) and phosphate ions have come to rule cell signaling.( Clapham E D)10 Calcium ions are important signaling molecules, as once they enter the cytoplasm they exert allosteric regulatory effects on many enzymes and proteins. Calcium can act in signal transduction resulting from activation of ion channels or as a second messenger caused by indirect signal transduction pathways such as G protein-coupled receptors.
  • 3.  Calcium signaling through ion channels  Movement of calcium ions from the extracellular compartment to the intracellular compartment alters membrane potential. This is seen in the heart, during the plateau phase of ventricular contraction. In this example, calcium acts to maintain depolarization of the heart. Calcium signaling through ion channels is also important in neuronal synaptic transmission.
  • 4.  Calcium as a secondary messenger  Important physiological roles for calcium signaling range widely. These include muscle contraction, neuronal transmission as in an excitatory synapse, cellular motility (including the movement of flagella and cilia), fertilization, cell growth or proliferation, learning and memory as with synaptic plasticity, and secretion of saliva.1 Other biochemical roles of calcium include regulating enzyme activity, permeability of ion channels, activity of ion pumps, and components of the cytoskeleton.2 The resting concentration of Ca2+ in the cytoplasm is normally maintained in the range of 10–100 nM. To maintain this low concentration, Ca2+ is actively pumped from the cytosol to the extracellular space and into the endoplasmic reticulum (ER), and sometimes in the mitochondria. Certain proteins of the cytoplasm and organelles act as buffers by binding Ca2+. Signaling occurs when the cell is stimulated to release calcium ions (Ca2+) from intracellular stores, and/or when calcium enters the cell through plasma membrane ion channels.3
  • 5.  Specific signals can trigger a sudden increase in the cytoplasmic Ca2+ level up to 500–1,000 nM by opening channels in the endoplasmic reticulum or the plasma membrane. The most common signaling pathway that increases cytoplasmic calcium concentration is the phospholipase C pathway. Many cell surface receptors, including G protein-coupled receptors and receptor tyrosine kinases activate the phospholipase C (PLC) enzyme. PLC hydrolyses the membrane phospholipid PIP2 to form IP3 and diacylglycerol (DAG), two classical second messengers. DAG activates the protein kinase C enzyme, while IP3 diffuses to the endoplasmic reticulum, binds to its receptor (IP3 receptor), which is a Ca2+ channel, and thus releases Ca2+ from the endoplasmic reticulum.
  • 6.  Depletion of calcium from the endoplasmic reticulum will lead to Ca2+ entry from outside the cell by activation of "Store-Operated Channels" (SOCs). This inflowing calcium current that results after stored calcium reserves have been released is referred to as Ca2+-releaseactivated Ca2+ current (ICRAC). The mechanisms through which ICRAC occurs are currently still under investigation, although two candidate molecules, Orai1 and stroma interaction molecule 1 (STIM1), have been linked by several studies, and a model of store-operated calcium influx, involving these molecules, has been proposed. Recent studies have cited the phospholipase A2 beta,4 nicotinic acid adenine dinucleotide phosphate (NAADP),5 and the protein STIM 16 as possible mediators of ICRAC.
  • 7.  Many of Ca2+-mediated events occur when the released Ca2+ binds to and activates the regulatory protein calmodulin. Calmodulin may activate calcium-calmodulin-dependent protein kinases, or may act directly on other effector proteins. Besides calmodulin, there are many other Ca2+-binding proteins that mediate the biological effects of Ca2+.  In neurons, concomitant increases in cytosolic and mitochondrial calcium are important for the synchronization of neuronal electrical activity with mitochondrial energy metabolism. Mitochondrial matrix calcium levels can reach the tens of micromolar levels, which is necessary for the activation of isocitrate dehydrogenase, one of the key regulatory enzymes of the Kreb's cycle.7 8
  • 8.  Calcium ions play an important role in cell signaling, especially with regards to the ER. In the neuron, the ER may serve in a network integrating numerous extracellular and intracellular signals in a binary membrane system with the plasma membrane. Such an association with the plasma membrane creates the relatively new perception of the ER and theme of “a neuron within a neuron.” The ER’s structural characteristics, ability to act as a Ca2+ sink, and specific CCa2+ releasing proteins, serve to create a system that may produce regenerative waves of Ca2+ release that may communicate both locally and globally in the cell. These Ca2+ signals, integrating extracellular and intracellular fluxes, have been implicated to play roles in synaptic plasticity and memory, neurotransmitter release, neuronal excitability and long term changes at the gene transcription level. ER stress is also related to Ca2+ signaling and along with the unfolded protein response, can cause ER associated degradation (ERAD) and autophagy.9
  • 9. Calcium Signaling Tool Kit:   The calcium signaling network can be divided in to     four functional units as shown in figure 3. 1: Signaling is triggered by a stimulus that generates various Ca2+ mobilizing. 2: This activates the ON mechanisms that feed Ca2+ into the cytoplasm. 3: Ca2+ functions as a messenger to stimulate numerous Ca2+ sensitive processes. 4: The OFF mechanisms are composed of pumps and exchangers which remove Ca2+ ions from the cytoplasm to restore the resting state as shown in figure 4.( Berridge 2000)11
  • 10. Recent Roles of Calcium The metastasis of cancer is the main cause of mortality in cancer patients.In metastasis tumour enters the circulation and establishes cancer cell growth in different organs. The second messenger Ca2+ ion is a crucial regulation of cell migration. recently a number of molecular players in cellular calcium homeostasis which include Ca2+ release activated calcium channel protein 1,stroma interactions molecule 1 and transient receptor potential channel have been Implicated in tumour cell migration and the metastatic cell phenotype. (Prevarskaya N et al 2011).12 Cerella C et al (2010)13 described the dual role of calcium as messenger and stressor in cell damage, death and survival. It was described that Ca2+ ion is an important second messenger participating in many cellular activities. The physicochemical insult to the cell deregulates the delicate homeostasis of calcium. This acts as intracellular stressor and producing increased cell damage. This damage can result in cell death or in case of survival the cellular repair can occur. The responses are mediated through Ca2+ as second messenger.
  • 11. Literature Cited  Berridge, Michael J.; Lipp, Peter, Bootman, Martin D. (October 2000). "The versatility and universality of calcium signalling". Nature Reviews Molecular Cell Biology 1 (1): 11–21. doi:10.1038/35036035. PMID 11413485.  Koolman, Jan; Röhm, Klaus-Heinrich (2005). Color Atlas of Biochemistry. New York: Thieme. ISBN 1-58890247-1.  Clapham, D.E. (2007). "Calcium Signaling". Cell 131 (6): 1047–1058. doi:10.1016/j.cell.2007.11.028. PMID 18083096.  Csutora, P.; et al. (2006). "Activation Mechanism for CRAC Current and Store-operated Ca2+ Entry". Journal of Biological Chemistry 281 (46): 34926–34935. doi:10.1074/jbc.M606504200. PMID 17003039.  Moccia, F.; et al. (2003). "NAADP activates a Ca2+ current that is dependent on F-actin cytoskeleton". The FASEB Journal 17 (13): 1907–1909. doi:10.1096/fj.03-0178fje. PMID 12923070.  Baba, Y.; et al. (2006). "Coupling of STIM1 to store-operated Ca2+ entry through its constitutive and inducible movement in the endoplasmic reticulum". PNAS 103 (45): 16704–16709. doi:10.1073/pnas.0608358103. PMC 1636519. PMID 17075073.  Ivannikov, M. et al. (2013). "Mitochondrial Free Ca2+ Levels and Their Effects on Energy Metabolism in Drosophila Motor Nerve Terminals". Biophys. J. 104 (11): 2353–2361. PMID 23746507.  Ivannikov, M. et al. (2013). "Synaptic vesicle exocytosis in hippocampal synaptosomes correlates directly with total mitochondrial volume". J. Mol. Neurosci. 49 (1): 223–230. PMID 22772899.  Berridge, M. (1998). "Neuronal calcium signaling". Neuron 21 (1): 13–26. doi:10.1016/S0896-6273(00)80510-3. PMID 9697848.  Clapham E D ,Castaneada R A (2007). Calcium Signaling. Cell 131. 1047-1058  11.Berridge MJ ,Lipp P and Bootman DM (2000).The Versatility And Universality Of Calcium Signaling. Nature Reviews /Molecular Cells Biology.(1): 11 – 21.  12. Prevarskaya N,Skryma R and Shuba (2011).Calcium in Tumour Metastasis: New Roles for Known Actors Nature Reviews (11): 609-618.  13. Cerella C, Diederich M & Ghibelly L (2010) International Journal of Cell Biology (2010): Article ID 546163 DOI: 10.1155/2010/546163.
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