Calcium, sodium, potassium, and magnesium ions after translocation through ion channels or by transport proteins can cause activation of release processes, contractile proteins, adenylate and guanylate cyclase, phosphodiesterases, protein kinases, phospholipases, ATPases and other enzymes. Receptors of various types and various toxins serve to modulate ion channels and generation of second messengers including cyclic nucleotides, diacylglycerides, arachidonic acid and phosphatidic acid. Modulatory interactions or """"""""cross-talk"""""""" occurs both between the second messenger systems and with the ion transport systems. Maitotoxin, a marine polyether increases phospholipid breakdown, leading to inositol phosphate and diacyclglyceride production. The primary site of action of maitotoxin appears to be a calcium channel. The maitotoxin-responses are effectively blocked by imidazoles that are also effective in blocking the so-called calcium-release-activated calcium (CRAC) channels, which are activated in plasma membranes of cells when IP3-sensitive intracellular stores of calcium are depleted either through receptor- activation of phospholipase C or through blockade of intracellular Ca++- ATPases by thapsigargin. However, other calcium blockers that prevent maitotoxin-responses do not block CRAC channels activated by ATP or fmLP in HL-60 cells. These include fluspirilene, penfluridol, loperamide and proadifen. The imidazoles (econazole, miconazole, SKF 96365, clotrimazole, calmidazolim) not only block maitotoxin-responses and CRAC channels, but also elicit per se an influx of calcium. Loperamide, while having no effect on [Ca2+]; alone, appears to enhance CRAC channel- elicited influx. ATP activates phosphoinositide breakdown in HL-60 cells through a P2u-receptor. In PC12 cells, ATP activates phosphoinositide breakdown through both P2u and P2y-receptors. In addition, ATP triggers calcium influx in PC12 cells through another P2-receptor. Activation of P2y- but not P2u-receptors leads to a sustained elevation of intracellular calcium presumably via CRAC channels, an activation of calcium-dependent potassium channels and release of norepinephrine.
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