Intracellular Calcium Signaling

Despite tremendous diversities in their expression, cellular activities in virtually all cell types are regulated by common intracellular signaling systems, and calcium is one important ubiquitous intracellular messenger, controlling a diverse range of cellular processes, such as gene transcription, muscle contraction and cell proliferation (Ref.1). In response to adequate stimuli, [Ca2+]i (Intracellular Ca2+ concentration) increases, oscillates and decreases, leading to the activation, modulation and termination of cell function. Numerous channels and pumps allow this particular cation to enter and exit cells and move between the cytosol and intracellular stores.

The Ca2+ signaling apparatus includes 1) the RyR (Ryanodine Receptor Channels) that is the SR (Sarcoplasmic Reticulum) Ca2+ release channel, 2) the Troponin protein complex that mediates the Ca2+ effect to the myofibrillar structures leading to contraction, 3) the Ca2+ pump responsible for Ca2+ reuptake into the SR, and 4) Calsequestrin, the Ca2+ storage protein in the SR. In addition, a multitude of Ca2+-binding proteins is present in muscle tissue including annexins, sorcin, myosin light chains, β-Actinin, Caln (Calcineurin), and Calpain (Ref.2). When calcium signaling is stimulated in a cell, Ca2+ enters the cytoplasm from one of two general sources: it is released from intracellular stores, or it enters the cell across the plasma membrane. The mechanism of regulated Ca2+ entry in non-excitable cells is through a process known as capacitative Ca2+ entry or store-operated Ca2+ entry, in which the depletion of intracellular stores due to the action of IP3 (Inositol Trisphosphate) or other Ca2+-releasing signals activates a signaling pathway leading to the opening of plasma membrane Ca2+ channels (Ref.3). In excitable cells, the major pathway for Ca2+ influx is via highly Ca2+-selective VGCC (Voltage-Gated Ca2+ Channels). In skeletal muscle cells, an additional voltage-sensitive pathway is provided by DHPR (Dihydropyridine Receptors) that is physically coupled to RyR on the Sarco- and ER (Endoplasmic Reticulum) membrane. Many Ligand-Gated Ionotropic Channels NMDA (N-methyl-D-aspartate), AMPA (α-Amino-3-Hydroxy-5-Methyl-4-Isoxazole Proprionate), Kainate, AchR (Nicotinic Acetylcholine Receptor), Serotonin (5HT3), and ATP (P2X) admit significant amounts of Ca2+ through its receptors. Store Operated Channels open in response to emptying of intracellular stores through the interaction with IP3 and its receptor (IP3R). CRAC (Ca2+-Release-Activated Ca2+ channel) is found in cells of the blood lineage and is highly Ca2+-selective. TRP (Transient Receptor Potential) are nonspecific cation channels, which is subdivided into three groups TRPC, TRPV and TRPM. TRPC channels respond indirectly to Hormones and Transmitters through PLC-β (Phospholipase-C) activation and via second messengers such as DAG (Diacylglycerol), Spinghosine, ADP-Ribose, Arachidonic Acid and other unidentified signals. TRPV and TRPM families are directly or indirectly responsive to numerous sensory stimuli such as temperature and Osmolarity (Ref.4 & 6).

Other voltage-independent channels respond to sensory stimuli. Hair cells of the ear have mechanically opened Ca2+-permeant channels. Light, Odorants and Taste molecules operate through a signal cascade that includes activation of AC (Adenyl Cyclase) and GC (Guanylate Cyclase), and subsequent opening or closing of CNG (Cyclic Nucleotide Gated) Channels whose gating is regulated by the cyclic nucleotides cAMP (cyclic Adenosine 3', 5’-Monophosphate) or cGMP (cyclic Guanosine Monophosphate) through G-proteins; GN-αS, GN-αT and GN-α-Olf. Voltage-independent pathways are generally activated by signaling cascades and the most common pathway involves activation of PLC and generation of IP3 and DAG from PIP2 (Phosphatidylinositol (4, 5)-Bisphosphate). Hormones and Neurotransmitters bind to GPCR (G-Protein Coupled Receptors). Both the heterotrimeric GN-αQ/GN-α11 and GN-αI/GN-αO proteins regulate the function of PLC-β. GPCR coupling to GN-αI/GN-αO activate PLC-β, through the GN-β and GN-γ subunits that are liberated in large quantities (Ref.7). Other members of the PLC family are activated by Growth Factors that activate RTK (Receptor Tyrosine Kinases; PLC-γ), Ras (PLC-Epsilon), and intracellular Ca2+ (PLC-Delta). PLC-γ is also activated by Antigen-stimulated activation of non-RTKs such as Src via binding to TCRs (T-Cell Receptors) and BCRs (B-Cell Receptors) (Ref.6). Ca2+ release from the intracellular stores is mediated by RyR and IP3R channels. RyR are activated by a rise in intracellular CICR (Ca2+-Ca2+ Induced Ca2+ Release). In addition there are RyR-like channels activated by cADPR (cyclic ADP-ribose) (Ref.5), Sphingosine and a distinct Ca2+-release pathway activated by NAADP (Nicotinic Acid Adenine Dinucleotide Phosphate). Within Ca2+-storing organelles, Ca2+ ions are bound to specialized Ca2+-buffering proteins like CS (Calsequestrins), CR (Calreticulins) and CN (Calnexins). In the cytosol, there are mobile Ca2+ buffers; the CB (Calbindins), PV (Paravalbumin), Calm (Calmodulin) and S100 protein families that blunt Ca2+ spikes and assist in redistribution of Ca2+ ions (Ref.6).

In contrast to the striking variety of mechanisms for inducing extracellular Ca2+ influx, Ca2+ extrusion to the extracellular space is largely limited to two families of proteins: the PMCA (Plasma Membrane Ca2+ ATPase) and the NCX (Na+/Ca2+ Exchanger). Intracellular Ca2+ is also lowered by Ca2+ uptake into cellular organelles via a variety of organelle-specific pumps and transporters. Uptake into the ER is regulated by the SERCA (Sarco- and Endoplasmic Reticulum Ca2+ ATPase) family. Uptake into mitochondria is mediated by the mitochondrial Ca2+-Uniporter and uptake into Golgi is mediated by the PMR1/ATP2C1 (P-type Ca2+-transport ATPase). Mitochondria release Ca2+ via the mitochondrial NHE (Na+-H+/Ca2+ Exchanger) and, under some circumstances, the PTP (Permeability Transition Pore) (Ref.6). Cytoplasmic Ca2+ signals propagate to the nucleus, where they directly stimulate the synthesis of immediate early genes as well as structural genes. Activation of Ca2+-dependent transcription requires both cytoplasmic and nuclear Ca2+ signals. Ca2+ influx through synaptic NMDA Receptors activates CREB (c-AMP Response Element-Binding Protein), whereas influx through extrasynaptic NMDA Receptors inhibits CREB. Ligand-Gated Channels use the cytoplasmic Ca2+ sensor, Calm (Calmodulin), to sense local Ca2+ elevations and activate a PKA-dependent Rap1-MAPK/ERK (Mitogen-Activated Protein Kinase/ Extracellular Signal-Regulated Kinase) Pathway (Ref.8). CalmKII and CalmKIV (Calm Kinase-II and IV) phosphorylation of CBP (CREB Binding Protein) and Histone Deacetylases, HDAC4, HDAC5 and HDAC7 mediate some nuclear Ca2+ signals. HDAC export allows MEF2 (Myocyte Enhancing Factor-2) to activate transcription by recruiting other Ca2+-sensitive transcriptional factors such as NFAT (Nuclear Factor of Activated T-Cells) and transcriptional coactivators such as p300 in the CRE (cAMP Responsive Element) region. Nuclear Ca2+ also activates Caln, which dephosphorylates NFAT and promotes its transcriptional activity (Ref.9).

Ca2+ is an important early messenger that is important for wound repair and for the initiation of cellular events such as the fertilization of oocytes, muscle contraction and hormone and peptide secretion (Ref.10). Buffering of intracellular Ca2+ transients in human neutrophils leads to reduced motility due to defective uropod detachment on fibronectin and vitronectin-coated surfaces. Recently, subtler forms functional alterations of several Ca2+ signaling and handling molecules have been found to be responsible for the pathophysiological conditions seen in dystrophinopathies, Brody's disease, certain forms of myopathies (related to channel malfunctioning), and malignant hyperthermia (related to Ca2+-releasing RyR mechanisms) (Ref.2). The degeneration of the retina is caused by gene defects of neuronal calcium sensors. Calpain has also been involved in a number of diseases like the limb girdle muscular dystrophy Type 2A (Calpain-III), and the Type 2 Diabetes (Ref.11).

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