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. Maitotoxin (MTX), a ladder-like polyether of molecular weight 3424, activates calcium uptake and phosphoinositide breakdown in all cells studied to date. Activation of phospholipase C by MTX is dependent on extracellular calcium. A blocker of receptor-mediated calcium entry, SK&F 96365, antagonized in a similar dose-response relationship MTX-elicited calcium influx, MTX-elicited phosphoinositide breakdown and MTX-elicited insulin release in cultured cells. Thus, it appears that the primary effect of MTX is to activate directly the SK&F 96365-sensitive so-called receptor-mediated calcium entry system and, thereby, increase internal calcium, activate phosphoinositide breakdown and trigger release of hormones and neurotransmitters. MTX does not act as an ionophore and stimulates uptake of other cations to a much lesser degree than calcium. Binding data suggests a high affinity membrane site. Thin-layer chromatography in combination with fast-atom bombardment mass spectrometry was shown to be ideally suited for identification and analysis of molecular species of phospholipids. Bis(monoacylglycero)phosphates were identified as significant membrane phospholipids in pheochromocytoma cells. Phosphatidylcholine was shown to be the major substrate for phorbol ester and bradykinin-activated phospholipase D in such cells.
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