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. Maitotoxin-elicited influx of calcium was blocked by imidazoles (SKf 96365, econazole, miconazole, clotrimazole) that also effectively block the so-called calcium release-activated calcium (CRAC) channels. Such imidazoles have proven to be the only class of compounds that block CRAC channels, but there were many other compounds that effectively blocked maitotoxin-elicited influx of calcium. Some of the more potent versus maitotoxin were fluspirilene, penfluridol, loperamide, RMI 12330A, and proadifen. Thus, maitotoxin does not appear to act primarily through effects on CRAC channels. Loperamide was found to be unique in enhancing influx of calcium via CRAC channels that had been activated either by a receptor-mediated release of intracellular calcium or by thapsigargin-mediated depletion of intracellular pools of calcium. The stimulatory effects of loperamide have been demonstrated in several cell lines. A series of quaternary amines have been prepared to probe the structural requisites for blockade of potassium channels by the classical blocker tetraethylammonium.
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