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Calcium Signaling Pathway

Calcium (Ca2+) serves as a ubiquitous second messenger in all eukaryotes. For an ever-increasing number of biological processes, it has been found that temporally and spatially defined changes of Ca2+ concentration in the cytoplasm or in defined organelles occur at one point or another. The importance of Ca2+ signaling pathway for the implementation of the information provided by Ca2+ has been increasingly appreciated, and several distinct families of Ca2+ sensing proteins have been identified and characterized.

An Overview of Calcium Signaling Pathway

Ca2+ is a highly versatile intracellular signal capable of regulating many different processes. Its distribution in intra-and extracellular spaces makes specialized pumps and channels necessary for its functioning and mobilization, as well as the influence of the cell depolarization or repolarization. Furthermore, the amount and duration of the flow of Ca2+ will determine the type and duration of its effect on intracellular signaling. Ca2+ signaling not only governs intracellular regulation but also appears to contribute to long distance or even organismic signal propagation and physiological response regulation. Ca2+ signaling is shaped by an intimate interplay of channels and transporters, and the important contributing individual components have been identified and characterized. It is translated by an elaborate toolkit of Ca2+-binding proteins, many of which function as Ca2+ sensors, into defined downstream responses.

Ca2+ signaling pathway occurs between cells in two ways:

  • First, cellular Ca2+ autonomy can be circumvented by gap junction (connexin) channels, as it  often occurs in epithelium and cardiomyocytes.
  • Second, more commonly, cell-to-cell signaling is effected by transmitter-gated, usually Ca2+ permeant, ion channels (e.g., NMDA, nicotinic, purinergic ionotropic). Voltage-gated Ca2+ channels (CaV) rapidly increase periplasmic Ca2+ that in turn trigger protein-fusion machines (e.g., synaptotagmins and SNARE complexes), enabling vesicles containing transmitter molecules to fuse to the plasma membrane. Small molecules (ATP, acetylcholine) and single amino acids (e.g., glutamate) released outside the cell gate Ca2+-permeant channels (P2X, nicotinic receptors, NMDA receptors) on adjacent cell membranes. These Ca2+-mediated events dominate much of neuroscience, and corollaries are now appreciated in extracellular communication between almost all cell types.

The Ca2+-permeant ion channels

Figure 1. The Ca2+-permeant ion channels.

Process and Regulation of Calcium Signaling Pathway

G protein-coupled receptor (GPCR) activates phospholipase C β (PLC β) and RTK activates PLC γ cleave phosphatidylinositol 4, 5 bisphosphate (PIP2) into 1, 4, 5-inositol trisphosphate (IP3) and diacylglycerol (DAG). Ca2+ binds to the C2 domain of PKCα, β1, β2, and γ subtypes initiate translocation to the membrane, where coincident DAG binding activates Protein kinase C (PKC). Ca2+-sensitive DAG kinase phosphorylates DAG to produce phosphatidic acid, while DAG lipase converts DAG to arachidonic acid, thus to generate a host of bioactive molecules.

Ca2+ can be directly released into the nucleoplasm via IP3 receptor (IP3R) and ryanodine receptor (RYR). The Ca2+ -sensitive protein phosphatase calcineurin (CaN) activates the transcription factor NFAT, which plays a critical role in Ca2+ signaling pathway process. Several different transcription factors and their upstream kinases are regulated by calcium. However, transcription is often not directly controlled by calcium ions but requires the involvement of specific signaling molecules and adaptors, which are activated by calcium inside or outside the nucleus. Thus, several routes exist by which calcium can relay a message to the nuclear transcription machinery. For example, the presence of nuclear calcium has been demonstrated as a requirement for the induction of activity-dependent, cAMP response element binding protein (CREB)-mediated gene transcription. One of the most widely occupied routes is the calcium-mediated activation of protein kinase cascades in the cytoplasm such as forming Calmodulin (CALM) to CaMKII and CaMKIV and their subsequent translocation into the nucleus.

The ERK1/2-MAPK cascade is a major target of synaptically evoked calcium signals, during which Ras and PKC are required to yield physiologically relevant activity of ERK1/2 through activating Raf and MEK1/2. PKC regulates CARMA1-Bcl 10- Malt1 signalosome to activate IKK, which releases transcription factor (p50/p65) from IKB. ERK1, p50 and p65 play an important role in gene expression and control the activity of many different intracellular signaling substrates in the nucleus.

Calcium Signaling Pathway in Physiology

Ca2+ signaling pathway operates in many different modes, thus enabling it to function over a wide dynamic range. It can trigger exocytosis at synaptic endings within microseconds and muscle contraction in milliseconds, whereas, at the other end of the scale, it can operate over minutes to hours to drive processes such as gene transcription and cell proliferation. A wide range of Ca2+ signaling pathways deliver the spatial and temporal Ca2+ signals necessary to control the specific functions of different cell types. The release of Ca2+ by InsP3 (inositol 1/4/5-trisphosphate) plays a central role in many of these signaling pathways. Ongoing transcriptional processes maintain the integrity and stability of these cell-specific signaling pathways. However, these homoeostatic systems are highly plastic and can undergo a process of phenotypic remodeling, resulting in the Ca2+ signals being set either too high or too low. Such subtle dysregulation of Ca2+ signals has been linked to some of the major diseases in humans such as cardiac-disease, schizophrenia, bipolar disorder (BD) and Alzheimer’s disease (AD).

References:

1. Berridge, M.J. Calcium signalling remodelling and disease. Biochemical Society Award.2012, 40(2):297-309.

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