Calcium (Ca2+)
Introduction
Ca2+ is a vital second messenger in cells, and it regulates many events in a cell such as gene transcription. Cytoplasmic Ca2+ can be elevated in cells either by release from internal stores located in the ER or by entry across the plasma membrane. Many signals from the extracellular miliu, from adjacent cells, or from a distant part of the cell itself can cause a calcium transient, which is a sharp rise in the cytoplasmic CA2+concentration. Intracellular calcium concentration is tightly regulated, and numerous cellular constituents (e.g., proteins) are calcium sensitive.
Ca2+ Signaling Mechanisms
Calcium transients can be achieved through Ca2+ channels in the plasma membrane (PM) or those in the endoplasmic reticulum (ER), which functions as an intracellular Ca2+ store.
An important mechanisms of Ca2+ release involves the phosphoinositide (PI) pathway, where PM receptors of the G-protein-linked or tyrosine kinase families activate specific phospholipase C (PLC) isoforms, resulting in the cleavage of phosphatidylinositol 4,5-bisphosphate (PIP2) into diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). In the case of Ca2+ release from the ER, IP3 is critical because it opens a specific calcium channel in the ER called Ip3 receptor (IP3R).
Calcium Levels
Under physiological conditions, normal cytosolic calcium concentrations in a cell are about 100 nM, and normal extracellular calcium concentrations are generally about 1 MM.
Ca2+ and Immunoreceptor Signalling
T-cell receptor (TCR), B-cell receptor and various Fc receptors, collectively called the immunoreceptors, initiate signaling pathways that culminate in immunological effector functions. Antigen-mediate aggregation of the immunoreceptors triggers tyrosine phosphorylation of these receptors, adaptors and other substrates, leading ultimately to the generation of IP3 which bind to IP3 receptors in the ER and cause rapid but transient release of Ca2+ from ER stores to the cytoplasm.
Once these Ca2+ stores are emptied, the entry of extracellular Ca2+ into the cell is activated through store-operated Ca2+ (SOC) channels in the PM. Thus the key feature of SOC entry is that it is the fall in Ca2+ content in the ER and not the subsequent rise in concentration of cytoplasmic Ca2+ that activates the channel.
Ca2+ influx through SOC channels results in sustained increase in concentration of free cytoplasmic Ca2+which leads to the activation of numerous signaling pathways, including calmodulin-dependent protein kinase II and the calmodulin activated serine threonine phosphatase calcineurin. Calcineurin, in turn, dephosphorylates the nuclear factor of activated T cells (NFAT) in the cytosol, inducing its activation and translation to the nucleus.
75% of all activation regulated genes in T cells show a dependence on Ca2+ inclux through the SOC channels in the PM. At short times, Ca2+ signals help to stabilize contacts between T cell and APC through changes in motility and cytoskeletal reorganization. Over period of minutes to hours, Ca2+ signals increase the efficiency and specificity of gene activation events.
Regulation of Calcium level in a cell
STIM-2: When basal calcium levels are low, the EF-hand domain of this protein is not bound by calcium, and STIM-2 forms aggregates in cell membranes (e.g., in the ER plasma membrane, allowing an influx of calcium into the cytoplasmic compartment. When basal calcium levels are high and calcium is bound to the EF hand domain, the protein does not aggregate and is spread in a more diffuse pattern in cell membranes and does not allow influx of calcium into the cytoplasm.