The role of calcium can also be duplicated by other relatively small cations like cobalt and nickel. Before becoming active in digestion, the proform of PLA2 is activated by Trypsin. PLA2 can also be characterized as having a channel featuring a hydrophobic wall in which hydrophobic amino acid residues such as Phe, Leu, and Tyr serve to bind the substrate. Another component of PLA2 is the seven disulfide bridges that are influential in regulation and stable protein folding. Biological Effects PLA2 action can release histamine from rat peritoneal mast cells. It also causes histamine release in human basophils. Regulation Due to the importance of PLA2 in inflammatory responses, regulation of the enzyme is essential. cPLA2 is regulated by phosphorylation and calcium concentrations. cPLA2 is phosphorylated by a MAPK at Serine-505. When phosphorylation is coupled with an influx of calcium ions, cPLA2 becomes stimulated and can translocate to the membrane to begin catalysis. Phosphorylation of cPLA2 may be a result of ligand binding to receptors, including: 5-HT2 receptors mGLUR1 bFGF receptor IFN-α receptor IFN-γ receptor In the case of an inflammation, the application of glucocorticoids up-regulate (mediated at the gene level) the production of the protein lipocortin which may inhibit cPLA2 and reduce the inflammatory response. Relevance in neurological disorders In normal brain cells, PLA2 regulation accounts for a balance between arachidonic acid's conversion into proinflammatory mediators and its reincorporation into the membrane. In the absence of strict regulation of PLA2 activity, a disproportionate amount of proinflammatory mediators are produced. The resulting induced oxidative stress and neuroinflammation is analogous to neurological diseases such as Alzheimer's disease, epilepsy, multiple sclerosis, ischemia. Lysophospholipids are another class of molecules released from the membrane that are upstream predecessors of platelet activating factors (PAF). Abnormal levels of potent PAF are also associated with neurological damage. An optimal enzyme inhibitor would specifically target PLA2 activity on neural cell membranes already under oxidative stress and potent inflammation. Thus, specific inhibitors of brain PLA2 could be a pharmaceutical approach to treatment of several disorders associated with neural trauma. Increase in phospholipase A2 activity is an acute-phase reaction that rises during inflammation, which is also seen to be exponentially higher in low back disc herniations compared to rheumatoid arthritis. It is a mixture of inflammation and substance P that are responsible for pain. Increased phospholipase A2 has also been associated with neuropsychiatric disorders such as schizophrenia and pervasive developmental disorders